Oza, B.
Eisen, T.
Frangou, E.
Stewart, G.D.
Bex, A.
Ritchie, A.W.
Kaplan, R.
Smith, B.
Davis, I.D.
Stockler, M.R.
Albiges, L.
Escudier, B.
Larkin, J.
Joniau, S.
Hancock, B.
Hermann, G.G.
Bellmunt, J.
Parmar, M.K.
Royston, P.
Meade, A.
(2022). External Validation of the 2003 Leibovich Prognostic Score in Patients Randomly Assigned to SORCE, an International Phase III Trial of Adjuvant Sorafenib in Renal Cell Cancer. ,
Vol.40
(16),
pp. 1772-1782.
show abstract
PURPOSE: The 2003 Leibovich score guides prognostication and selection to adjuvant clinical trials for patients with locally advanced renal cell carcinoma (RCC) after nephrectomy. We provide a robust external validation of the 2003 Leibovich score using contemporary data from SORCE, an international, randomized trial of sorafenib after excision of primary RCC. METHODS: Data used to derive the 2003 Leibovich score were compared with contemporary data from SORCE. Discrimination and calibration of the metastasis-free survival outcome were assessed in data from patients with clear-cell RCC, using Cox proportional hazards regression, Kaplan-Meier curves, and calculation of Harrell's c indexes. Secondary analyses involved three important SORCE groups: patients with any non-clear-cell subtype, papillary, and chromophobe carcinomas. RESULTS: Four hundred seven recurrences occurred in 982 patients in the Leibovich cohort and 520 recurrences were recorded in 1,445 patients in the primary SORCE cohort. Clear discrimination between intermediate-risk and high-risk SORCE cohorts was shown; hazard ratio 2.74 (95% CI, 2.29 to 3.28), c-index 0.63 (95% CI, 0.61 to 0.65). A hazard ratio of 0.61 (95% CI, 0.53 to 0.70) confirmed poor calibration of the two cohorts. Discrimination was observed in secondary populations, with c-indexes of 0.64 (95% CI, 0.59 to 0.69) for non-clear-cell RCC, 0.63 (95% CI, 0.56 to 0.69) for papillary RCC, and 0.65 (95% CI, 0.55 to 0.76) for chromophobe RCC. CONCLUSION: The 2003 Leibovich score discriminates between intermediate-risk and high-risk clear-cell and non-clear-cell RCC groups in contemporary data, supporting its use for risk stratification in adjuvant clinical trials. Over time, metastasis-free survival for patients with locally advanced RCC has improved. Contemporary data from adjuvant RCC trials should be used to improve prognostication for patients with RCC..
Giles, R.
Maskens, D.
Bick, R.
Martinez, R.
Packer, M.
Heng, D.
Larkin, J.
Bex, A.
Jewett, M.
Jonasch, E.
MacLennan, S.
(2022). Patient-reported Experience of Diagnosis, Management, and Burden of Renal Cell Carcinomas: Results from a Global Patient Survey in 43 Countries. ,
Vol.37,
pp. 3-6.
show abstract
The International Kidney Cancer Coalition (IKCC) is a federation of 46 affiliated patient organisations representing 1.2 million patients worldwide that is committed to reducing the global burden of kidney cancer. A large-scale global survey of patients with renal cell carcinoma (RCC) to capture real-world experiences has never been undertaken. The 35-question survey was designed to identify geographic variations in patient education, experience, awareness, access to care, best practices, quality of life, and unmet psychosocial needs. A total of 1983 responses were recorded from 43 countries in 14 languages. Analysis revealed key findings. (1) At diagnosis, 43% of all respondents had no understanding of their RCC subtype. (2) Shared decision-making remains aspirational: globally, 29% of all patients reported no involvement in their treatment decision, responding "My doctor decided for me". (3) While 96% of respondents reported psychosocial impacts, surprisingly, only 50% disclosed them to their health care team. (4) Lastly, 70% of patients were not asked to participate in a clinical trial, although 90% indicated they would be interested. The survey reflects patient perspectives from diverse clinical scenarios in which different treatment options are available. The data point to actionable deficits in the fields of clinical trials, psychosocial support, and shared decision-making. PATIENT SUMMARY: In this brief report, we highlight the key results from the first large-scale global survey of patients with kidney cancer to capture real-world experiences. This survey reflects patient perspectives from diverse clinical scenarios in which different treatment options are available. We conclude that there is a need for improvement in the fields of clinical trials, psychosocial support, and shared decision-making..
Kennedy, O.J.
Kicinski, M.
Valpione, S.
Gandini, S.
Suciu, S.
Blank, C.U.
Long, G.V.
Atkinson, V.G.
Dalle, S.
Haydon, A.M.
Meshcheryakov, A.
Khattak, A.
Carlino, M.S.
Sandhu, S.
Larkin, J.
Puig, S.
Ascierto, P.A.
Rutkowski, P.
Schadendorf, D.
Koornstra, R.
Hernandez-Aya, L.
Di Giacomo, A.M.
van den Eertwegh, A.J.
Grob, J.-.
Gutzmer, R.
Jamal, R.
van Akkooi, A.C.
Robert, C.
Eggermont, A.M.
Lorigan, P.
Mandala, M.
(2022). Prognostic and predictive value of β-blockers in the EORTC 1325/KEYNOTE-054 phase III trial of pembrolizumab versus placebo in resected high-risk stage III melanoma. ,
Vol.165,
pp. 97-112.
show abstract
BACKGROUND: β-adrenergic receptors are upregulated in melanoma cells and contribute to an immunosuppressive, pro-tumorigenic microenvironment. This study investigated the prognostic and predictive value of β-adrenoreceptor blockade by β-blockers in the EORTC1325/KEYNOTE-054 randomised controlled trial. METHODS: Patients with resected stage IIIA, IIIB or IIIC melanoma and regional lymphadenectomy received 200 mg of adjuvant pembrolizumab (n = 514) or placebo (n = 505) every three weeks for one year or until recurrence or unacceptable toxicity. At a median follow-up of 3 years, pembrolizumab prolonged recurrence-free survival (RFS) compared to placebo (hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.47-0.68). β-blocker use was defined as oral administration of any β-blocker within 30 days of randomisation. A multivariable Cox proportional hazard model was used to estimate the HR for the association between the use of β-blockers and RFS. RESULTS: Ninety-nine (10%) of 1019 randomised patients used β-blockers at baseline. β-blockers had no independent prognostic effect on RFS: HR 0.96 (95% CI 0.70-1.31). The HRs of RFS associated with β-blocker use were 0.67 (95% CI 0.38-1.19) in the pembrolizumab arm and 1.15 (95% CI 0.80-1.66) in the placebo arm. The HR of RFS associated with pembrolizumab compared to placebo was 0.34 (95% CI 0.18-0.65) among β-blocker users and 0.59 (95% CI 0.48-0.71) among those not using β-blockers. CONCLUSIONS: This study suggests no prognostic effect of β-blockers in resected high-risk stage III melanoma. However, β-blockers may predict improved efficacy of adjuvant pembrolizumab treatment. The combination of immunotherapy with β-blockers merits further investigation. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37..
Pires da Silva, I.
Ahmed, T.
McQuade, J.L.
Nebhan, C.A.
Park, J.J.
Versluis, J.M.
Serra-Bellver, P.
Khan, Y.
Slattery, T.
Oberoi, H.K.
Ugurel, S.
Haydu, L.E.
Herbst, R.
Utikal, J.
Pföhler, C.
Terheyden, P.
Weichenthal, M.
Gutzmer, R.
Mohr, P.
Rai, R.
Smith, J.L.
Scolyer, R.A.
Arance, A.M.
Pickering, L.
Larkin, J.
Lorigan, P.
Blank, C.U.
Schadendorf, D.
Davies, M.A.
Carlino, M.S.
Johnson, D.B.
Long, G.V.
Lo, S.N.
Menzies, A.M.
(2022). Clinical Models to Define Response and Survival With Anti-PD-1 Antibodies Alone or Combined With Ipilimumab in Metastatic Melanoma. J clin oncol,
Vol.40
(10),
pp. 1068-1080.
show abstract
PURPOSE: Currently, there are no robust biomarkers that predict immunotherapy outcomes in metastatic melanoma. We sought to build multivariable predictive models for response and survival to anti-programmed cell death protein 1 (anti-PD-1) monotherapy or in combination with anticytotoxic T-cell lymphocyte-4 (ipilimumab [IPI]; anti-PD-1 ± IPI) by including routine clinical data available at the point of treatment initiation. METHODS: One thousand six hundred forty-four patients with metastatic melanoma treated with anti-PD-1 ± IPI at 16 centers from Australia, the United States, and Europe were included. Demographics, disease characteristics, and baseline blood parameters were analyzed. The end points of this study were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). The final predictive models for ORR, PFS, and OS were determined through penalized regression methodology (least absolute shrinkage and selection operator method) to select the most significant predictors for all three outcomes (discovery cohort, N = 633). Each model was validated internally and externally in two independent cohorts (validation-1 [N = 419] and validation-2 [N = 592]) and nomograms were created. RESULTS: The final model for predicting ORR (area under the curve [AUC] = 0.71) in immunotherapy-treated patients included the following clinical parameters: Eastern Cooperative Oncology Group Performance Status, presence/absence of liver and lung metastases, serum lactate dehydrogenase, blood neutrophil-lymphocyte ratio, therapy (monotherapy/combination), and line of treatment. The final predictive models for PFS (AUC = 0.68) and OS (AUC = 0.77) included the same variables as those in the ORR model (except for presence/absence of lung metastases), and included presence/absence of brain metastases and blood hemoglobin. Nomogram calculators were developed from the clinical models to predict outcomes for patients with metastatic melanoma treated with anti-PD-1 ± IPI. CONCLUSION: Newly developed combinations of routinely collected baseline clinical factors predict the response and survival outcomes of patients with metastatic melanoma treated with immunotherapy and may serve as valuable tools for clinical decision making..
Schmitt, A.M.
Dumas, L.
Larkin, J.
(2022). Atezolizumab, cobimetinib, and vemurafenib as first-line treatment for unresectable metastatic BRAF V600 mutated melanoma. Expert rev anticancer ther,
Vol.22
(1),
pp. 17-25.
show abstract
INTRODUCTION: The treatment of metastatic melanoma has been revolutionized by the introduction of immune checkpoint inhibitors and BRAF/MEK inhibition. Nevertheless, almost half of patients will progress or show primary resistance to treatment. The combination of BRAF/MEK and immune checkpoint inhibition might achieve higher response rates and improve long-term disease control. The IMspire150 trial investigated the combination of atezolizumab, cobimetinib and vemurafenib versus cobimetinib and vemurafenib alone. AREAS COVERED: This review covers the efficacy and safety of atezolizumab, cobimetinib and vemurafenib for patients with advanced or metastatic BRAF mutant melanoma. The combination is compared with the current standard of care including BRAF/MEK inhibition and treatment with immune checkpoint inhibitors. EXPERT OPINION: Atezolizumab plus cobimetinib and vemurafenib showed superior progression-free survival in metastatic melanoma compared to cobimetinib and vemurafenib alone. Triplet therapy might be an option in situations of urgent need for disease control, when oncologists choose BRAF/MEK inhibition over immune checkpoint inhibition as first line treatment. At this time results are not mature yet, and longer follow-up including overall survival data is needed. The future role of this combination will also be determined by a comparison with the combination of ipilimumab and nivolumab..
Shum, B.
Larkin, J.
Turajlic, S.
(2022). Predictive biomarkers for response to immune checkpoint inhibition. Seminars in cancer biology,
Vol.79,
pp. 4-17.
Homicsko, K.
Dummer, R.
Hoeller, C.
Wolchok, J.D.
Hodi, F.S.
Larkin, J.
Ascierto, P.A.
Atkinson, V.
Robert, C.
Postow, M.A.
Re, S.
Paulucci, D.
Dobler, D.
Michielin, O.
(2022). Proton Pump Inhibitor Use and Efficacy of Nivolumab and Ipilimumab in Advanced Melanoma. ,
Vol.14
(9),
p. 2300.
show abstract
The impact of proton pump inhibitors (PPIs) on clinical outcomes with first-line immune checkpoint inhibitors (ICIs) in patients with metastatic melanoma was previously analyzed in the phase II study, CheckMate 069. This retrospective analysis utilized data from three phase II/III studies of first-line ICI therapy in untreated advanced melanoma: CheckMate 066, 067, and 069. All randomized patients with PPI use ≤ 30 days before initiating study treatment were included in the PPI-use subgroup. Possible associations between baseline PPI use and efficacy were evaluated within each treatment arm of each study using multivariable modeling. Approximately 20% of 1505 randomized patients across the studies reported baseline PPI use. The median follow-up was 52.6-58.5 months. Objective response rate (ORR), progression-free survival (PFS), and overall survival analyses provided insufficient evidence of a meaningful association between PPI use and efficacy outcomes with nivolumab-plus-ipilimumab, nivolumab, or ipilimumab therapy. In five of the six ICI treatment arms, 95% confidence intervals for odds ratios or hazard ratios traversed 1. Significant associations were observed in the CheckMate 069 combination arm between PPI use and poorer ORR and PFS. This multivariable analysis found insufficient evidence to support meaningful associations between PPI use and ICI efficacy in patients with advanced melanoma..
Rini, B.I.
Moslehi, J.J.
Bonaca, M.
Schmidinger, M.
Albiges, L.
Choueiri, T.K.
Motzer, R.J.
Atkins, M.B.
Haanen, J.
Mariani, M.
Wang, J.
Hariharan, S.
Larkin, J.
(2022). Prospective Cardiovascular Surveillance of Immune Checkpoint Inhibitor-Based Combination Therapy in Patients With Advanced Renal Cell Cancer: Data From the Phase III JAVELIN Renal 101 Trial. ,
Vol.40
(17),
pp. 1929-1938.
show abstract
PURPOSE: Both immune checkpoint inhibitors (ICIs) and vascular endothelial growth factor receptor (VEGFR) inhibitors are approved for advanced renal cell carcinoma treatment and can cause cardiovascular events (CVs); thus, combination therapy could lead to major adverse CV events (MACE). Cardiac serum biomarker assessment and imaging, including left ventricular ejection fraction (LVEF) monitoring, can be used to evaluate MACE. METHODS: To our knowledge, the JAVELIN Renal 101 trial, assessing avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma, is the first randomized study of ICI plus VEGFR inhibitor treatment to include prospective serial cardiac monitoring of LVEF and serum cardiac biomarkers. RESULTS: MACE (defined as grade ≥ 3 CV AEs) occurred in 31 patients (7.1%) in the combination arm and 17 patients (3.9%) in the sunitinib arm. Patients in the combination arm who had high baseline troponin T values were at higher risk of MACE versus patients with low values (MACE in 6/35 v 7/135, respectively; relative risk, 3.31; 95% CI, 1.19 to 9.22). This association was not observed in patients treated with sunitinib. Other CV baseline risk factors and serum cardiac biomarkers were not significantly predictive for MACE, although a trend toward an association with dyslipidemia was seen in the combination arm. No clinical value of on-treatment routine monitoring of LVEF in relation to MACE was observed. Although LVEF decline was significantly more frequent in the combination arm, most patients recovered, and decline was not associated with other significant cardiac events or symptoms. CONCLUSION: Patients with high baseline troponin T levels receiving ICI and VEGFR combinations may need to be monitored more closely for MACE. Routine monitoring of LVEF in asymptomatic patients is not recommended..
Larkin, J.
Weber, J.
Del Vecchio, M.
Gogas, H.
Arance, A.M.
Dalle, S.
Cowey, C.L.
Schenker, M.
Grob, J.-.
Chiarion-Sileni, V.
Márquez-Rodas, I.
Butler, M.O.
Di Giacomo, A.M.
Middleton, M.R.
De la Cruz-Merino, L.
Arenberger, P.
Atkinson, V.
Hill, A.
Fecher, L.A.
Millward, M.
Khushalani, N.I.
Queirolo, P.
Long, G.V.
Lobo, M.
Askelson, M.
Ascierto, P.A.
Mandalá, M.
(2022). Adjuvant nivolumab versus ipilimumab (CheckMate 238 trial): Reassessment of 4-year efficacy outcomes in patients with stage III melanoma per AJCC-8 staging criteria. ,
Vol.173,
pp. 285-296.
show abstract
PURPOSE: Nivolumab was approved as adjuvant therapy for melanoma based on data from CheckMate 238, which enrolled patients per American Joint Committee on Cancer version 7 (AJCC-7) criteria. Here, we analyse long-term outcomes per AJCC-8 staging criteria compared with AJCC-7 results to inform clinical decisions for patients diagnosed per AJCC-8. PATIENTS AND METHODS: In a double-blind, phase 3 trial (NCT02388906), patients aged ≥15 years with resected, histologically confirmed AJCC-7 stage IIIB, IIIC, or IV melanoma were randomised to receive nivolumab 3 mg/kg every 2 weeks or ipilimumab 10 mg/kg every 3 weeks for 4 doses and then every 12 weeks, both intravenously ≤1 year. Recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) were assessed in patients with stage III disease, per AJCC-7 and AJCC-8. RESULTS: Per AJCC-7 staging, 42.4% and 57.3% of patients were in substage IIIB and IIIC, respectively; per AJCC-8, 1.1%, 30.4%, 62.8%, and 5.0% were in IIIA, IIIB, IIIC, and IIID. After 4 years' minimum follow-up, the AJCC-7 superior efficacy of nivolumab over ipilimumab in patients with resected stage III melanoma was preserved per AJCC-8 analysis. No statistically significant difference in RFS between stage III substage hazard ratios was observed per AJCC-7 or -8 staging criteria (interaction test: AJCC-7, P = 0.8115; AJCC-8, P = 0.1051; P = 0.8392 ((AJCC-7) and P = 0.8678 (AJCC-8) for DMFS). CONCLUSIONS: CheckMate 238 4-year RFS and DMFS outcomes are consistent per AJCC-7 and AJCC-8 staging criteria. Outcome benefits can therefore be translated for patients diagnosed per AJCC-8..
Bilen, M.A.
Rini, B.I.
Voss, M.H.
Larkin, J.
Haanen, J.B.
Albiges, L.
Pagliaro, L.C.
Voog, E.G.
Lam, E.T.
Kislov, N.
McGregor, B.A.
Lalani, A.-.
Huang, B.
di Pietro, A.
Krulewicz, S.
Robbins, P.B.
Choueiri, T.K.
(2022). Association of Neutrophil-to-Lymphocyte Ratio with Efficacy of First-Line Avelumab plus Axitinib vs Sunitinib in Patients with Advanced Renal Cell Carcinoma Enrolled in the Phase 3 JAVELIN Renal 101 Trial. ,
Vol.28
(4),
pp. 738-747.
show abstract
PURPOSE: To evaluate the association between neutrophil-to-lymphocyte ratio (NLR) and efficacy of avelumab plus axitinib or sunitinib. EXPERIMENTAL DESIGN: Adult patients with untreated advanced renal cell carcinoma (RCC) with a clear-cell component, ≥1 measurable lesions, Eastern Cooperative Oncology Group performance status of 0 or 1, fresh or archival tumor specimen, and adequate renal, cardiac, and hepatic function were included. Retrospective analyses of the association between baseline NLR and progression-free survival (PFS) and overall survival (OS) in the avelumab plus axitinib or sunitinib arms were performed using the first interim analysis of the phase 3 JAVELIN Renal 101 trial (NCT02684006). Multivariate Cox regression analyses of PFS and OS were conducted. Translational data were assessed to elucidate the underlying biology associated with differences in NLR. RESULTS: Patients with below-median NLR had longer observed PFS with avelumab plus axitinib [stratified HR, 0.85; 95% confidence interval (CI), 0.634-1.153] or sunitinib (HR, 0.56; 95% CI, 0.415-0.745). In the avelumab plus axitinib or sunitinib arms, respectively, median PFS was 13.8 and 11.2 months in patients with below-median NLR, and 13.3 and 5.6 months in patients with median-or-higher NLR. Below-median NLR was also associated with longer observed OS in the avelumab plus axitinib (HR, 0.51; 95% CI, 0.300-0.871) and sunitinib arms (HR, 0.30; 95% CI, 0.174-0.511). Tumor analyses showed an association between NLR and key biological characteristics, suggesting a role of NLR in underlying mechanisms influencing clinical outcome. CONCLUSIONS: Current data support NLR as a prognostic biomarker in patients with advanced RCC receiving avelumab plus axitinib or sunitinib..
Yngvadottir, B.
Andreou, A.
Bassaganyas, L.
Larionov, A.
Cornish, A.J.
Chubb, D.
Saunders, C.N.
Smith, P.
Zhang, H.
Cole, Y.
Consortium, G.E.
Larkin, J.
Browning, L.
Turajlic, S.
Litchfield, K.
Houlston, R.S.
Maher, E.R.
(2022). Frequency of pathogenic germline variants in cancer susceptibility genes in 1336 renal cell carcinoma cases. ,
,
p. ddac089.
show abstract
BACKGROUND: Renal cell carcinoma (RCC) occurs in a number of cancer predisposition syndromes but the genetic architecture of susceptibility to RCC is not well defined. We investigated the frequency of pathogenic germline variants in cancer susceptibility genes (CSGs) within a large series of unselected RCC participants. METHODS: Whole genome sequencing data on 1336 RCC participants and 5834 controls recruited to the UK 100000 Genomes Project, a nationwide multicentre study, was analysed to identify rare pathogenic or likely pathogenic (P/LP) short variants (SNVs and INDELs) and structural variants in 121 CSGs. RESULTS: Among 1336 RCC participants (mean 61.3 years [±12SD], range 13-88 years; 64% male), 85 participants (6.4%; 95% CI [5.1, 7.8]) had one or more P/LP germline variant in a wider range of CSGs than previously recognised. A further 64 intragenic variants in CSGs previously associated with RCC were classified as a variant of uncertain significance (VUS) (24 'hot VUSs') and were considered to be of potential clinical relevance as further evaluation might result in their reclassification. Most patients with pathogenic variants in well-established RCC-CSGs were aged < 50 years. Burden test analysis for filtered variants in CSGs demonstrated a significant excess of CHEK2 variants RCC European participants compared to the healthy European controls (P = 0.0019). CONCLUSIONS: Approximately 6% of patients with RCC unselected for family history have a germline variant requiring additional follow-up analysis. To improve diagnostic yield we suggest expanding the panel of RCC-CSGs tested to include CHEK2 and all SDHx subunits and raising the eligibility criteria for age-based testing..
Lee, C.-.
Motzer, R.J.
Glen, H.
Michaelson, M.D.
Larkin, J.
Minoshima, Y.
Kanekiyo, M.
Ikezawa, H.
Sachdev, P.
Dutcus, C.E.
Funahashi, Y.
Voss, M.H.
(2021). Correlative serum biomarker analyses in the phase 2 trial of lenvatinib-plus-everolimus in patients with metastatic renal cell carcinoma. British journal of cancer,
Vol.124
(1),
pp. 237-246.
show abstract
Background No biomarkers have been established to predict treatment efficacy in renal cell carcinoma (RCC). In an exploratory retrospective analysis of a Phase 2 study, we constructed composite biomarker scores (CBSs) to predict progression-free survival (PFS) and overall survival (OS) in patients with metastatic RCC randomised to receive lenvatinib-plus-everolimus.Methods Of 40 biomarkers tested, the 5 most strongly associated with PFS (HGF, MIG, IL-18BP, IL-18, ANG-2) or OS (TIMP-1, M-CSF, IL-18BP, ANG-2, VEGF) were used to make a 5-factor PFS-CBS or OS-CBS, respectively. A 2-factor CBS was generated with biomarkers common to PFS-CBS and OS-CBS. Patients were divided into groups accordingly (5-factor-CBS high: 3-5, CBS-low: 0-2; 2-factor-CBS high: 1-2, CBS-low: 0).Results PFS/OS with lenvatinib-plus-everolimus were significantly longer in the 5-factor CBS-high group versus the CBS-low group (P = 0.0022/P < 0.0001, respectively). In the CBS-high group, PFS/OS were significantly longer with lenvatinib-plus-everolimus versus everolimus (P < 0.001/P = 0.0079, respectively); PFS was also significantly longer with lenvatinib-plus-everolimus versus lenvatinib (P = 0.0046). The 5-factor-CBS had a predictive role in PFS and OS after multivariate analysis. Similar trends were observed with the 2-factor-CBS for PFS (i.e., lenvatinib-plus-everolimus versus everolimus).Conclusions The 5-factor CBS may identify patients with metastatic RCC who would benefit from lenvatinib-plus-everolimus versus everolimus; additional validation is required.Clinical trial registration The clinical trial registration number is NCT01136733..
Regan, M.M.
Mantia, C.M.
Werner, L.
Tarhini, A.A.
Larkin, J.
Stephen Hodi, F.
Wolchok, J.
Postow, M.A.
Stwalley, B.
Moshyk, A.
Ritchings, C.
Re, S.
van Dijck, W.
McDermott, D.F.
Atkins, M.B.
(2021). Treatment-free survival over extended follow-up of patients with advanced melanoma treated with immune checkpoint inhibitors in CheckMate 067. ,
Vol.9
(11),
p. e003743.
show abstract
BACKGROUND: Treatment-free survival (TFS) characterizes disease control after discontinuation of immune checkpoint inhibitors (ICIs) until subsequent therapy or death. We previously evaluated TFS in a pooled analysis of the CheckMate 067 and CheckMate 069 trials of the ICIs nivolumab and ipilimumab, alone or in combination, in patients with advanced melanoma after minimum follow-up of 36 months. This analysis investigated TFS differences between treatments in CheckMate 067 after a minimum follow-up of 60 months, and their relation to overall survival (OS) differences. METHODS: Data were from 937 patients who initiated treatment (nivolumab plus ipilimumab, nivolumab, or ipilimumab) in CheckMate 067 (NCT01844505). TFS was defined as the area between the Kaplan-Meier curves for time to protocol therapy cessation and time to subsequent systemic therapy initiation or death, each measured from randomization. TFS was partitioned as time with and without toxicity. Toxicity included persistent and late-onset grade ≥2 select treatment-related adverse events (ie, those of potential immunologic etiology). The area between Kaplan-Meier curves was estimated by the difference in 60-month restricted-mean times of the endpoints. Between-group differences were estimated with bootstrapped 95% CIs. RESULTS: At 60 months from randomization, 39%, 24%, and 11% of patients assigned to treatment with nivolumab plus ipilimumab, nivolumab, and ipilimumab, respectively, had survived and were treatment-free. The 60-month mean TFS was approximately twice as long with the combination (19.7 months) than with nivolumab (9.9 months; absolute difference, 9.8 (95% CI 6.7 to 12.8)) or ipilimumab (11.9 months; absolute difference, 7.8 (95% CI 4.6 to 11.0)). In the respective groups, mean TFS represented 33% (8% with and 25% without toxicity), 17% (2% and 14%), and 20% (3% and 17%) of the 60-month period. Compared with 36-month estimates, mean TFS over the 60-month period represented slightly greater percentages of time in the nivolumab-containing regimen groups and a lesser percentage in the ipilimumab group. TFS differences between the combination and either monotherapy increased with longer follow-up. CONCLUSIONS: Along with improved long-term OS with the nivolumab-containing regimens versus ipilimumab, TFS without toxicity was sustained with nivolumab plus ipilimumab versus either monotherapy, demonstrating larger between-group differences with extended follow-up..
Hodi, F.S.
Wolchok, J.D.
Schadendorf, D.
Larkin, J.
Long, G.V.
Qian, X.
Saci, A.
Young, T.C.
Srinivasan, S.
Chang, H.
Tang, H.
Wind-Rotolo, M.
Rizzo, J.I.
Jackson, D.G.
Ascierto, P.A.
(2021). TMB and Inflammatory Gene Expression Associated with Clinical Outcomes following Immunotherapy in Advanced Melanoma. ,
Vol.9
(10),
pp. 1202-1213.
show abstract
Outcomes for patients with melanoma have improved over the past decade as a result of the development and FDA approval of immunotherapies targeting cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1), and programmed death ligand 1 (PD-L1). However, these therapies do not benefit all patients, and an area of intensive research investigation is identifying biomarkers that can predict which patients are most likely to benefit from them. Here, we report exploratory analyses of the associations of tumor mutational burden (TMB), a 4-gene inflammatory gene expression signature, and BRAF mutation status with tumor response, progression-free survival, and overall survival in patients with advanced melanoma treated as part of the CheckMate 066 and 067 phase III clinical trials evaluating immuno-oncology therapies. In patients enrolled in CheckMate 067 receiving the anti-PD-1 inhibitor nivolumab (NIVO) alone or in combination with the anti-CTLA-4 inhibitor ipilimumab (IPI) or IPI alone, longer survival appeared to associate with high (>median) versus low (≤median) TMB and with high versus low inflammatory signature scores. For NIVO-treated patients, the results regarding TMB association were confirmed in CheckMate 066. In addition, improved survival was observed with high TMB and absence of BRAF mutation. Weak correlations were observed between PD-L1, TMB, and the inflammatory signature. Combined assessment of TMB, inflammatory gene expression signature, and BRAF mutation status may be predictive for response to immune checkpoint blockade in advanced melanoma..
Ascierto, P.A.
Dréno, B.
Larkin, J.
Ribas, A.
Liszkay, G.
Maio, M.
Mandalà, M.
Demidov, L.
Stroyakovskiy, D.
Thomas, L.
de la Cruz-Merino, L.
Atkinson, V.
Dutriaux, C.
Garbe, C.
Hsu, J.
Jones, S.
Li, H.
McKenna, E.
Voulgari, A.
McArthur, G.A.
(2021). 5-Year Outcomes with Cobimetinib plus Vemurafenib in BRAFV600 Mutation-Positive Advanced Melanoma: Extended Follow-up of the coBRIM Study. ,
Vol.27
(19),
pp. 5225-5235.
show abstract
PURPOSE: The randomized phase III coBRIM study (NCT01689519) demonstrated improved progression-free survival (PFS) and overall survival (OS) with addition of cobimetinib to vemurafenib compared with vemurafenib in patients with previously untreated BRAFV600 mutation-positive advanced melanoma. We report long-term follow-up of coBRIM, with at least 5 years since the last patient was randomized. PATIENTS AND METHODS: Eligible patients were randomized 1:1 to receive either oral cobimetinib (60 mg once daily on days 1-21 in each 28-day cycle) or placebo in combination with oral vemurafenib (960 mg twice daily). RESULTS: 495 patients were randomized to cobimetinib plus vemurafenib (n = 247) or placebo plus vemurafenib (n = 248). Median follow-up was 21.2 months for cobimetinib plus vemurafenib and 16.6 months for placebo plus vemurafenib. Median OS was 22.5 months (95% CI, 20.3-28.8) with cobimetinib plus vemurafenib and 17.4 months (95% CI, 15.0-19.8) with placebo plus vemurafenib; 5-year OS rates were 31% and 26%, respectively. Median PFS was 12.6 months (95% CI, 9.5-14.8) with cobimetinib plus vemurafenib and 7.2 months (95% CI, 5.6-7.5) with placebo plus vemurafenib; 5-year PFS rates were 14% and 10%, respectively. OS and PFS were longest in patients with normal baseline lactate dehydrogenase levels and low tumor burden, and in those achieving complete response. The safety profile remained consistent with previously published reports. CONCLUSIONS: Extended follow-up of coBRIM confirms the long-term clinical benefit and safety profile of cobimetinib plus vemurafenib compared with vemurafenib monotherapy in patients with BRAFV600 mutation-positive advanced melanoma..
Mandala, M.
Larkin, J.
Ascierto, P.A.
Del Vecchio, M.
Gogas, H.
Cowey, C.L.
Arance, A.
Dalle, S.
Schenker, M.
Grob, J.-.
Chiarion-Sileni, V.
Marquez-Rodas, I.
Butler, M.O.
Di Giacomo, A.M.
Lutzky, J.
De La Cruz-Merino, L.
Atkinson, V.
Arenberger, P.
Hill, A.
Fecher, L.
Millward, M.
Khushalani, N.I.
de Pril, V.
Lobo, M.
Weber, J.
(2021). Adjuvant nivolumab for stage III/IV melanoma: evaluation of safety outcomes and association with recurrence-free survival. ,
Vol.9
(8),
p. e003188.
show abstract
BACKGROUND: Several therapeutic options are now available in the adjuvant melanoma setting, mandating an understanding of their benefit‒risk profiles in order to make informed treatment decisions. Herein we characterize adjuvant nivolumab select (immune-related) treatment-related adverse events (TRAEs) and evaluate possible associations between safety and recurrence-free survival (RFS) in the phase III CheckMate 238 trial. METHODS: Patients with resected stage IIIB-C or IV melanoma received nivolumab 3 mg/kg every 2 weeks (n=452) or ipilimumab 10 mg/kg every 3 weeks for four doses and then every 12 weeks (n=453) for up to 1 year or until disease recurrence, unacceptable toxicity, or consent withdrawal. First-occurrence and all-occurrence select TRAEs were analyzed within discrete time intervals: from 0 to 3 months of treatment, from >3-12 months of treatment, and from the last dose (regardless of early or per-protocol treatment discontinuation) to 100 days after the last dose. Possible associations between select TRAEs and RFS were investigated post randomization in 3-month landmark analyses and in Cox model analyses (including a time-varying covariate of select TRAE), within and between treatment groups. RESULTS: From the first nivolumab dose to 100 days after the last dose, first-occurrence select TRAEs were reported in 67.7% (306/452) of patients. First-occurrence select TRAEs were reported most frequently from 0 to 3 months (48.0%), during which the most common were pruritus (15.5%) and diarrhea (15.3%). Most select TRAEs resolved within 6 months. There was no clear association between the occurrence (or not) of select TRAEs and RFS by landmark analysis or by Cox model analysis within treatment arms or comparing nivolumab to the ipilimumab comparator arm. CONCLUSION: Results of this safety analysis of nivolumab in adjuvant melanoma were consistent with its established safety profile. In the discrete time intervals evaluated, most first-occurrence TRAEs occurred early during treatment and resolved. No association between RFS and select TRAEs was evident. TRIAL REGISTRATION NUMBER: NCT02388906..
Kostine, M.
Finckh, A.
Bingham, C.O.
Visser, K.
Leipe, J.
Schulze-Koops, H.
Choy, E.H.
Benesova, K.
Radstake, T.R.
Cope, A.P.
Lambotte, O.
Gottenberg, J.-.
Allenbach, Y.
Visser, M.
Rusthoven, C.
Thomasen, L.
Jamal, S.
Marabelle, A.
Larkin, J.
Haanen, J.B.
Calabrese, L.H.
Mariette, X.
Schaeverbeke, T.
(2021). EULAR points to consider for the diagnosis and management of rheumatic immune-related adverse events due to cancer immunotherapy with checkpoint inhibitors. ,
Vol.80
(1),
pp. 36-48.
show abstract
BACKGROUND: Rheumatic and musculoskeletal immune-related adverse events (irAEs) are observed in about 10% of patients with cancer receiving checkpoint inhibitors (CPIs). Given the recent emergence of these events and the lack of guidance for rheumatologists addressing them, a European League Against Rheumatism task force was convened to harmonise expert opinion regarding their identification and management. METHODS: First, the group formulated research questions for a systematic literature review. Then, based on literature and using a consensus procedure, 4 overarching principles and 10 points to consider were developed. RESULTS: The overarching principles defined the role of rheumatologists in the management of irAEs, highlighting the shared decision-making process between patients, oncologists and rheumatologists. The points to consider inform rheumatologists on the wide spectrum of musculoskeletal irAEs, not fulfilling usual classification criteria of rheumatic diseases, and their differential diagnoses. Early referral and facilitated access to rheumatologist are recommended, to document the target organ inflammation. Regarding therapeutic, three treatment escalations were defined: (1) local/systemic glucocorticoids if symptoms are not controlled by symptomatic treatment, then tapered to the lowest efficient dose, (2) conventional synthetic disease-modifying antirheumatic drugs, in case of inadequate response to glucocorticoids or for steroid sparing and (3) biological disease-modifying antirheumatic drugs, for severe or refractory irAEs. A warning has been made on severe myositis, a life-threatening situation, requiring high dose of glucocorticoids and close monitoring. For patients with pre-existing rheumatic disease, baseline immunosuppressive regimen should be kept at the lowest efficient dose before starting immunotherapies. CONCLUSION: These statements provide guidance on diagnosis and management of rheumatic irAEs and aim to support future international collaborations..
Ferguson, L.
Ho, B.
Weir, J.
Francis, N.
West, K.
Rathbone, B.
Larkin, J.
Heelan, K.
(2021). Extensive mucocutaneous, oesophageal and otic lichen planus secondary to nivolumab therapy. ,
Vol.1
(1),
p. e8.
show abstract
We report a 73-year-old female with metastatic renal cell carcinoma who developed a widespread lichenoid reaction following nivolumab treatment. The timeline of the reaction strongly correlated with the nivolumab treatment and subsequent cessation. Our patient had cutaneous, mucosal, otic, ophthalmic and oesophageal involvement, demonstrating the potentially extensive nature of lichenoid reactions to anti-programmed cell death receptor-1 (anti-PD1) therapies. Although lichenoid reactions to anti-PD1 therapies are now well recognized, there have been no previous reports of otic or oesophageal involvement in the literature. Although cutaneous lichenoid reactions do not tend to be severe or treatment limiting, more widespread systemic lichenoid reactions are challenging to manage, particularly in the context of malignancy. This very unusual case highlights the importance of considering involvement beyond the skin in all lichenoid skin reactions..
Saturno, G.
Lopes, F.
Niculescu-Duvaz, I.
Niculescu-Duvaz, D.
Zambon, A.
Davies, L.
Johnson, L.
Preece, N.
Lee, R.
Viros, A.
Holovanchuk, D.
Pedersen, M.
McLeary, R.
Lorigan, P.
Dhomen, N.
Fisher, C.
Banerji, U.
Dean, E.
Krebs, M.G.
Gore, M.
Larkin, J.
Marais, R.
Springer, C.
(2021). The paradox-breaking panRAF plus SRC family kinase inhibitor, CCT3833, is effective in mutant KRAS-driven cancers. Annals of oncology : official journal of the european society for medical oncology,
Vol.32
(2),
pp. 269-278.
show abstract
Background KRAS is mutated in ∼90% of pancreatic ductal adenocarcinomas, ∼35% of colorectal cancers and ∼20% of non-small-cell lung cancers. There has been recent progress in targeting G12C KRAS specifically, but therapeutic options for other mutant forms of KRAS are limited, largely because the complexity of downstream signaling and feedback mechanisms mean that targeting individual pathway components is ineffective.Design The protein kinases RAF and SRC are validated therapeutic targets in KRAS-mutant pancreatic ductal adenocarcinomas, colorectal cancers and non-small-cell lung cancers and we show that both must be inhibited to block growth of these cancers. We describe CCT3833, a new drug that inhibits both RAF and SRC, which may be effective in KRAS-mutant cancers.Results We show that CCT3833 inhibits RAF and SRC in KRAS-mutant tumors in vitro and in vivo, and that it inhibits tumor growth at well-tolerated doses in mice. CCT3833 has been evaluated in a phase I clinical trial (NCT02437227) and we report here that it significantly prolongs progression-free survival of a patient with a G12V KRAS spindle cell sarcoma who did not respond to a multikinase inhibitor and therefore had limited treatment options.Conclusions New drug CCT3833 elicits significant preclinical therapeutic efficacy in KRAS-mutant colorectal, lung and pancreatic tumor xenografts, demonstrating a treatment option for several areas of unmet clinical need. Based on these preclinical data and the phase I clinical unconfirmed response in a patient with KRAS-mutant spindle cell sarcoma, CCT3833 requires further evaluation in patients with other KRAS-mutant cancers..
Edwards, C.L.
Comito, F.
Agraso Busto, S.
Harland, C.
Turajlic, S.
Larkin, J.
Heelan, K.
Fearfield, L.
(2021). Cutaneous toxicities in patients with melanoma receiving checkpoint inhibitor therapy: a retrospective review The experience of a single large specialist institution. Clinical and experimental dermatology,
Vol.46
(2),
pp. 338-341.
Meric-Bernstam, F.
Larkin, J.
Tabernero, J.
Bonini, C.
(2021). Enhancing anti-tumour efficacy with immunotherapy combinations. The lancet,
Vol.397
(10278),
pp. 1010-1022.
Gogas, H.
Dréno, B.
Larkin, J.
Demidov, L.
Stroyakovskiy, D.
Eroglu, Z.
Francesco Ferrucci, P.
Pigozzo, J.
Rutkowski, P.
Mackiewicz, J.
Rooney, I.
Voulgari, A.
Troutman, S.
Pitcher, B.
Guo, Y.
Yan, Y.
Castro, M.
Mulla, S.
Flaherty, K.
Arance, A.
(2021). Cobimetinib plus atezolizumab in BRAFV600 wild-type melanoma: primary results from the randomized phase III IMspire170 study. Annals of oncology,
Vol.32
(3),
pp. 384-394.
Lidington, E.
Vlooswijk, C.
Stallard, K.
Travis, E.
Younger, E.
Edwards, P.
Nandhabalan, M.
Hunter, N.
Sarpal, N.
Flett, D.
Din, A.
Starling, N.
Larkin, J.
Stanway, S.
Nobbenhuis, M.
Banerjee, S.
Szucs, Z.
Darlington, A.-.
Gonzalez, M.
Sirohi, B.
van der Graaf, W.T.
Husson, O.
(2021). 'This is not part of my life plan': A qualitative study on the psychosocial experiences and practical challenges in young adults with cancer age 25 to 39 years at diagnosis. European journal of cancer care,
,
pp. e13458-?.
show abstract
Objective Adolescents and young adults with cancer face unique psychosocial and practical issues. However, patients across this group encounter different life experiences, cancer diagnoses and treatment settings given the tailored services for patients ages 15 to 24. Here, we qualitatively explore the psychosocial experiences and practical challenges of young adults (YAs) with cancer diagnosed between ages 25 and 39 in the United Kingdom.Methods We invited YAs diagnosed with cancer in the 5 years prior to enrolment at participating sites to take part in semi-structured interviews or focus groups. Transcripts were analysed using inductive thematic analysis. Two YA patients reviewed the results to ensure robustness.Results Sixty-five YAs with varied diagnoses participated. Participants struggled to balance work, childcare and financial solvency with treatment. The halt in family and work life as well as changes in image and ability threatened participants' identity and perceived 'normality' as a YA, however, these also stimulated positive changes. YAs experienced social isolation from friends and family, including children. Many struggled to cope with uncertainty around treatment outcomes and disease recurrence.Conclusion The disruption of family and work life can lead to age-specific issues in YAs diagnosed with cancer. Age-tailored psychological and practical services must be considered..
Litchfield, K.
Reading, J.L.
Puttick, C.
Thakkar, K.
Abbosh, C.
Bentham, R.
Watkins, T.B.
Rosenthal, R.
Biswas, D.
Rowan, A.
Lim, E.
Al Bakir, M.
Turati, V.
Guerra-Assunção, J.A.
Conde, L.
Furness, A.J.
Saini, S.K.
Hadrup, S.R.
Herrero, J.
Lee, S.-.
Van Loo, P.
Enver, T.
Larkin, J.
Hellmann, M.D.
Turajlic, S.
Quezada, S.A.
McGranahan, N.
Swanton, C.
(2021). Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition. ,
Vol.184
(3),
pp. 596-614.e14.
show abstract
Checkpoint inhibitors (CPIs) augment adaptive immunity. Systematic pan-tumor analyses may reveal the relative importance of tumor-cell-intrinsic and microenvironmental features underpinning CPI sensitization. Here, we collated whole-exome and transcriptomic data for >1,000 CPI-treated patients across seven tumor types, utilizing standardized bioinformatics workflows and clinical outcome criteria to validate multivariable predictors of CPI sensitization. Clonal tumor mutation burden (TMB) was the strongest predictor of CPI response, followed by total TMB and CXCL9 expression. Subclonal TMB, somatic copy alteration burden, and histocompatibility leukocyte antigen (HLA) evolutionary divergence failed to attain pan-cancer significance. Dinucleotide variants were identified as a source of immunogenic epitopes associated with radical amino acid substitutions and enhanced peptide hydrophobicity/immunogenicity. Copy-number analysis revealed two additional determinants of CPI outcome supported by prior functional evidence: 9q34 (TRAF2) loss associated with response and CCND1 amplification associated with resistance. Finally, single-cell RNA sequencing (RNA-seq) of clonal neoantigen-reactive CD8 tumor-infiltrating lymphocytes (TILs), combined with bulk RNA-seq analysis of CPI-responding tumors, identified CCR5 and CXCL13 as T-cell-intrinsic markers of CPI sensitivity..
Olofsson Bagge, R.
Ny, L.
Ascierto, P.A.
Hodi, F.S.
Larkin, J.
Robert, C.
Schachter, J.
Weber, J.S.
Long, G.V.
van Akkooi, A.C.
(2021). The efficacy of immunotherapy for in-transit metastases of melanoma: an analysis of randomized controlled trials. Melanoma research,
Vol.31
(2),
pp. 181-185.
Ho, B.
Larkin, J.
Heelan, K.
(2021). Checkpoint Inhibitor-associated Cutaneous Small Vessel Vasculitis: A Review of the Literature. Journal of immunotherapy,
Vol.44
(3),
pp. 118-121.
Bottomley, A.
Coens, C.
Mierzynska, J.
Blank, C.U.
Mandalà, M.
Long, G.V.
Atkinson, V.G.
Dalle, S.
Haydon, A.M.
Meshcheryakov, A.
Khattak, A.
Carlino, M.S.
Sandhu, S.
Puig, S.
Ascierto, P.A.
Larkin, J.
Lorigan, P.C.
Rutkowski, P.
Schadendorf, D.
Koornstra, R.
Hernandez-Aya, L.
Di Giacomo, A.M.
van den Eertwegh, A.J.
Grob, J.-.
Gutzmer, R.
Jamal, R.
van Akkooi, A.C.
Krepler, C.
Ibrahim, N.
Marreaud, S.
Kicinski, M.
Suciu, S.
Robert, C.
Eggermont, A.M.
Lesimple, T.
Maio, M.
Linette, G.
Mortier, L.
Svane, I.M.
Schachter, J.
Brown, M.
Hersey, P.
Barrow, C.
Kudchadkar, R.
Dutriaux, C.
Song, X.
Quaglino, P.
Queirolo, P.
Meier, F.
Stroyakovskiy, D.
Guillot, B.
Romero, P.L.
Bastholt, L.
Garbe, C.
Grange, F.
Mohr, P.
Algazi, A.
Bechter, O.
Hernberg, M.
Loquai, C.
Meiss, F.
Chiarion Sileni, V.
Bar-Sela, G.
Fitzharris, B.
Saiag, P.
Arnault, J.-.
Simon, J.-.
Stephens, R.
Baurain, J.-.
Lebbe, C.
Combemale, P.
Dummer, R.
Hauschild, A.
Parente, P.
Yamazaki, N.
Milhem, M.
Leccia, M.-.
Geoffrois, L.
Kretschmer, L.
Dunwoodie, E.
Walker, J.
Lotem, M.
Hendler, D.
Mackiewicz, A.
Sekulovic, L.
Dzienis, M.
Hospers, G.A.
Siano, M.
Hassel, J.
Corrie, P.
Passos, M.-.
Levin, M.
Hoeller, C.
Machet, L.
Hallmeyer, S.
Waterston, A.
Descamps, V.
Kiecker, F.
Aarts, M.
Schmidt, H.
Raimundo, A.
Nyakas, M.
Lacour, J.-.
Berking, C.
Ferrucci, P.F.
Jameson, M.
Kim, K.
Yokota, K.
Kerger, J.
Aubin, F.
Groenewegen, G.
Kapiteijn, H.
Boehncke, W.-.
Utikal, J.
Casasola, R.
Marshall, E.
Ferraresi, V.
Richtig, E.
Matkovic, S.
Inozume, T.
Crook, T.
McNeil, C.
Kiyohara, Y.
Avril, M.-.
Hein, R.
Terheyden, P.
Nathan, P.
Aoi, J.
Skytta, T.
Jouary, T.
Takenouchi, T.
Straume, O.
Martins, C.
Mukhametshina, G.
(2021). Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): health-related quality-of-life results from a double-blind, randomised, controlled, phase 3 trial. The lancet oncology,
Vol.22
(5),
pp. 655-664.
Eggermont, A.M.
Blank, C.U.
Mandalà, M.
Long, G.V.
Atkinson, V.G.
Dalle, S.
Haydon, A.M.
Meshcheryakov, A.
Khattak, A.
Carlino, M.S.
Sandhu, S.
Larkin, J.
Puig, S.
Ascierto, P.A.
Rutkowski, P.
Schadendorf, D.
Koornstra, R.
Hernandez-Aya, L.
Di Giacomo, A.M.
van den Eertwegh, A.J.
Grob, J.-.
Gutzmer, R.
Jamal, R.
Lorigan, P.C.
van Akkooi, A.C.
Krepler, C.
Ibrahim, N.
Marreaud, S.
Kicinski, M.
Suciu, S.
Robert, C.
Menzies, A.
Lesimple, T.
Maio, M.
Linette, G.
Brown, M.
Hersey, P.
Svane, I.M.
Mortier, L.
Schachter, J.
Barrow, C.
Kudchadkar, R.
Song, X.
Dutriaux, C.
Quaglino, P.
Meier, F.
Queirolo, P.
Stroyakovskiy, D.
Bastholt, L.
Guillot, B.
Garbe, C.
Ortiz Romero, P.L.
Grange, F.
Mohr, P.
Algazi, A.
Bechter, O.
Hernberg, M.
Arnault, J.-.
Saiag, P.
Loquai, C.
Meiss, F.
Simon, J.-.
Bar-Sela, G.
Chiarion Sileni, V.
Fitzharris, B.
McCrystal, M.
Parente, P.
Baurain, J.-.
Combemale, P.
Lebbe, C.
Hauschild, A.
Yamazaki, N.
Dummer, R.
Milhem, M.
Dzienis, M.
Walker, J.
Geoffrois, L.
Leccia, M.-.
Kretschmer, L.
Hendler, D.
Lotem, M.
Mackiewicz, A.
Sekulovic, L.
Dunwoodie, E.
Hoeller, C.
Machet, L.
Hassel, J.
Hospers, G.A.
Passos, M.-.
Levin, M.
Fehr, M.
Corrie, P.
Waterston, A.
Hallmeyer, S.
Schmidt, H.
Descamps, V.
Lacour, J.-.
Berking, C.
Kiecker, F.
Ferrucci, P.F.
Yokota, K.
Aarts, M.
Jameson, M.
Winge-Main, A.K.
Ferreira, P.
Kim, K.
McNeil, C.
Hofmann-Wellenhof, R.
Kerger, J.
Aubin, F.
Utikal, J.
Ferraresi, V.
Inozume, T.
Kiyohara, Y.
Groenewegen, G.
Kapiteijn, H.
Matkovic, S.
Boehncke, W.-.
Casasola, R.
Crook, T.
Marshall, E.
Skytta, T.
Avril, M.-.
Jouary, T.
Hein, R.
Terheyden, P.
Aoi, J.
Takenouchi, T.
Straume, O.
Martins, C.
Mukhametshina, G.
Nathan, P.
(2021). Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): distant metastasis-free survival results from a double-blind, randomised, controlled, phase 3 trial. The lancet oncology,
Vol.22
(5),
pp. 643-654.
Kohoutova, D.
Worku, D.
Aziz, H.
Teare, J.
Weir, J.
Larkin, J.
(2021). Malignant Melanoma of the Gastrointestinal Tract: Symptoms, Diagnosis, and Current Treatment Options. ,
Vol.10
(2),
p. 327.
show abstract
Malignant melanoma (MM) has become the fifth most frequent cancer in the UK. It is the most common carcinoma to metastasize to the gastrointestinal (GI) tract. MM particularly has an affinity to spread to the small bowel, which is followed by the involvement of the stomach and large intestine. Excellent endoscopic options including video capsule endoscopy and enteroscopy are available for a precise diagnosis of GI involvement by a metastatic MM. The complete surgical resection of GI metastatic MM in carefully selected patients not only provides symptom control, but has also been associated with an increase in overall survival. The approval of BRAF-targeted therapies and immune checkpoint inhibitors has transformed therapeutic approaches for patients with metastatic MM over the past decade. Currently, the overall survival of patients with advanced metastatic MM who have been treated with a combination of immunotherapeutic agents reaches 52% at five years. The role of surgery for patients with the metastatic involvement of the GI tract with MM is evolving in the era of effective systemic treatments..
Tarhini, A.A.
Toor, K.
Chan, K.
McDermott, D.F.
Mohr, P.
Larkin, J.
Hodi, F.S.
Lee, C.-.
Rizzo, J.I.
Johnson, H.
Moshyk, A.
Rao, S.
Kotapati, S.
Atkins, M.B.
(2021). A matching-adjusted indirect comparison of combination nivolumab plus ipilimumab with BRAF plus MEK inhibitors for the treatment of BRAF-mutant advanced melanoma☆. ,
Vol.6
(2),
p. 100050.
show abstract
BACKGROUND: Approved first-line treatments for patients with BRAF V600-mutant advanced melanoma include nivolumab (a programmed cell death protein 1 inhibitor) plus ipilimumab (a cytotoxic T lymphocyte antigen-4 inhibitor; NIVO+IPI) and the BRAF/MEK inhibitors dabrafenib plus trametinib (DAB+TRAM), encorafenib plus binimetinib (ENCO+BINI), and vemurafenib plus cobimetinib (VEM+COBI). Results from prospective randomized clinical trials (RCTs) comparing these treatments have not yet been reported. This analysis evaluated the relative efficacy and safety of NIVO+IPI versus DAB+TRAM, ENCO+BINI, and VEM+COBI in patients with BRAF-mutant advanced melanoma using a matching-adjusted indirect comparison (MAIC). PATIENTS AND METHODS: A systematic literature review identified RCTs for DAB+TRAM, ENCO+BINI, and VEM+COBI in patients with BRAF-mutant advanced melanoma. Individual patient-level data for NIVO+IPI were derived from the phase III CheckMate 067 trial (BRAF-mutant cohort) and restricted to match the inclusion/exclusion criteria of the comparator trials. Treatment effects for overall survival (OS) and progression-free survival (PFS) were estimated using Cox proportional hazards and time-varying hazard ratio (HR) models. Safety outcomes (grade 3 or 4 treatment-related adverse events) with NIVO+IPI and the comparators were compared. RESULTS: In the Cox proportional hazards analysis, NIVO+IPI showed improved OS compared with DAB+TRAM (HR = 0.53; 95% confidence interval [CI], 0.39-0.73), ENCO+BINI (HR = 0.60; CI, 0.42-0.85), and VEM+COBI (HR = 0.50; CI, 0.36-0.70) for the overall study period. In the time-varying analysis, NIVO+IPI was associated with significant improvements in OS and PFS compared with the BRAF/MEK inhibitors 12 months after treatment initiation. There were no significant differences between NIVO+IPI and BRAF/MEK inhibitor treatment from 0 to 12 months. Safety outcomes favored DAB+TRAM over NIVO+IPI, whereas NIVO+IPI was comparable to VEM+COBI. CONCLUSION: Results of this MAIC demonstrated durable OS and PFS benefits for patients with BRAF-mutant advanced melanoma treated with NIVO+IPI compared with BRAF/MEK inhibitors, with the greatest benefits noted after 12 months..
Percik, R.
Larkin, J.
Morganstein, D.L.
(2021). Endocrinopathies induced by immune checkpoint inhibitors: the need for clear endocrine diagnosis. The lancet oncology,
Vol.22
(7),
pp. 905-907.
Rzeniewicz, K.
Larkin, J.
Menzies, A.M.
Turajlic, S.
(2021). Immunotherapy use outside clinical trial populations: never say never?. Annals of oncology,
Vol.32
(7),
pp. 866-880.
Dearden, H.
Au, L.
Wang, D.Y.
Zimmer, L.
Eroglu, Z.
Smith, J.L.
Cuvietto, M.
Khoo, C.
Atkinson, V.
Lo, S.
Long, G.V.
Sandhu, S.
Ascierto, P.A.
Carlino, M.S.
Johnson, D.B.
Larkin, J.
Menzies, A.M.
(2021). Hyperacute toxicity with combination ipilimumab and anti-PD1 immunotherapy. European journal of cancer,
Vol.153,
pp. 168-178.
Hepner, A.
Atkinson, V.G.
Larkin, J.
Burrell, R.A.
Carlino, M.S.
Johnson, D.B.
Zimmer, L.
Tsai, K.K.
Klein, O.
Lo, S.N.
Haydon, A.
Bhave, P.
Lyle, M.
Pallan, L.
Pires da Silva, I.
Gerard, C.
Michielin, O.
Long, G.V.
Menzies, A.M.
(2021). Re-induction ipilimumab following acquired resistance to combination ipilimumab and anti–PD-1 therapy. European journal of cancer,
Vol.153,
pp. 213-222.
Uthayakumar, A.K.
Rudd, E.
Noy, M.
Weir, J.
Larkin, J.
Fearfield, L.
(2021). Severe progressive scarring pembrolizumab‐induced lichen planopilaris in a patient with metastatic melanoma. Australasian journal of dermatology,
Vol.62
(3),
pp. 403-406.
Carlino, M.S.
Larkin, J.
Long, G.V.
(2021). Immune checkpoint inhibitors in melanoma. The lancet,
Vol.398
(10304),
pp. 1002-1014.
Mendis, S.
Ealing, J.
Larkin, J.
Turajlic, S.
Carr, A.
Bronstein, A.
Kaski, D.
(2021). Isolated imbalance due to bilateral vestibular failure following immune checkpoint inhibitor administration: two cases. European journal of cancer,
Vol.156,
pp. 187-189.
Sarnaik, A.A.
Hamid, O.
Khushalani, N.I.
Lewis, K.D.
Medina, T.
Kluger, H.M.
Thomas, S.S.
Domingo-Musibay, E.
Pavlick, A.C.
Whitman, E.D.
Martin-Algarra, S.
Corrie, P.
Curti, B.D.
Oláh, J.
Lutzky, J.
Weber, J.S.
Larkin, J.M.
Shi, W.
Takamura, T.
Jagasia, M.
Qin, H.
Wu, X.
Chartier, C.
Graf Finckenstein, F.
Fardis, M.
Kirkwood, J.M.
Chesney, J.A.
(2021). Lifileucel, a Tumor-Infiltrating Lymphocyte Therapy, in Metastatic Melanoma. Journal of clinical oncology : official journal of the american society of clinical oncology,
,
pp. JCO2100612-?.
show abstract
Purpose Effective treatment options are limited for patients with advanced (metastatic or unresectable) melanoma who progress after immune checkpoint inhibitors and targeted therapies. Adoptive cell therapy using tumor-infiltrating lymphocytes has demonstrated efficacy in advanced melanoma. Lifileucel is an autologous, centrally manufactured tumor-infiltrating lymphocyte product.Methods We conducted a phase II open-label, single-arm, multicenter study in patients with advanced melanoma who had been previously treated with checkpoint inhibitor(s) and BRAF ± MEK targeted agents. Lifileucel was produced from harvested tumor specimens in central Good Manufacturing Practice facilities using a streamlined 22-day process. Patients received a nonmyeloablative lymphodepletion regimen, a single infusion of lifileucel, and up to six doses of high-dose interleukin-2. The primary end point was investigator-assessed objective response rate (ORR) per RECIST, version 1.1.Results Sixty-six patients received a mean of 3.3 prior therapies (anti-programmed death 1 [PD-1] or programmed death ligand 1 [PD-L1]: 100%; anticytotoxic T-lymphocyte-associated protein-4: 80%; BRAF ± MEK inhibitor: 23%). The ORR was 36% (95% CI, 25 to 49), with two complete responses and 22 partial responses. Disease control rate was 80% (95% CI, 69 to 89). Median duration of response was not reached after 18.7-month median study follow-up (range, 0.2-34.1 months). In the primary refractory to anti-PD-1 or PD-L1 therapy subset, the ORR and disease control rate were 41% (95% CI, 26 to 57) and 81% (95% CI, 66 to 91), respectively. Safety profile was consistent with known adverse events associated with nonmyeloablative lymphodepletion and interleukin-2.Conclusion Lifileucel demonstrated durable responses and addresses a major unmet need in patients with metastatic melanoma with limited treatment options after approved therapy, including the primary refractory to anti-PD-1 or PD-L1 therapy subset..
Nogueira, E.
Menon, A.
Dede, A.
Mitra, I.
Brock, C.
Larkin, J.
Morganstein, D.
(2021). Pituitary enlargement following ipilimumab without long term endocrine dysfunction. Current problems in cancer,
Vol.45
(6),
pp. 100710-100710.
Aeppli, S.
Schmaus, M.
Eisen, T.
Escudier, B.
Grünwald, V.
Larkin, J.
McDermott, D.
Oldenburg, J.
Porta, C.
Rini, B.I.
Schmidinger, M.
Sternberg, C.N.
Rothermundt, C.
Putora, P.M.
(2021). First-line treatment of metastatic clear cell renal cell carcinoma: a decision-making analysis among experts. ,
Vol.6
(1),
p. 100030.
show abstract
BACKGROUND: The treatment landscape of metastatic clear cell renal cell carcinoma (mccRCC) has been transformed by targeted therapies with tyrosine kinase inhibitors (TKI) and more recently by the incorporation of immune checkpoint inhibitors (ICI). Today, a spectrum of single agent TKI to TKI/ICI and ICI/ICI combinations can be considered and the choice of the best regimen is complex. MATERIALS AND METHODS: We performed an updated decision-making analysis among 11 international kidney cancer experts. Each expert provided their treatment strategy and relevant decision criteria in the first line treatment of mccRCC. After the collection of all input a list of unified decision criteria was determined and compatible decision trees were created. We used a methodology based on diagnostic nodes, which allows for an automated cross-comparison of decision trees, to determine the most common treatment recommendations as well as deviations. RESULTS: Diverse parameters were considered relevant for treatment selection, various drugs and drug combinations were recommended by the experts. The parameters, chosen by the experts, were performance status, International Metastatic renal cell carcinoma Database Consortium (IMDC) risk group, PD-L1 status, zugzwang and contraindication to immunotherapy. The systemic therapies selected for first line treatment were sunitinib, pazopanib, tivozanib, cabozantinib, ipilimumab/nivolumab or pembrolizumab/axitinib. CONCLUSION: A wide spectrum of treatment recommendations based on multiple decision criteria was demonstrated. Significant inter-expert variations were observed. This demonstrates how data from randomized trials are implemented differently when transferred into daily practice..
Oza, B.
Frangou, E.
Smith, B.
Bryant, H.
Kaplan, R.
Choodari-Oskooei, B.
Powles, T.
Stewart, G.D.
Albiges, L.
Bex, A.
Choueiri, T.K.
Davis, I.D.
Eisen, T.
Fielding, A.
Harrison, D.
McWhirter, A.
Mulhere, S.
Nathan, P.
Rini, B.
Ritchie, A.
Scovell, S.
Shakeshaft, C.
Stockler, M.R.
Thorogood, N.
Parmar, M.K.
Larkin, J.
Meade, A.
(2021). RAMPART: A phase III multi-arm multi-stage trial of adjuvant checkpoint inhibitors in patients with resected primary renal cell carcinoma (RCC) at high or intermediate risk of relapse. ,
Vol.108,
p. 106482.
show abstract
BACKGROUND: 20-60% of patients with initially locally advanced Renal Cell Carcinoma (RCC) develop metastatic disease despite optimal surgical excision. Adjuvant strategies have been tested in RCC including cytokines, radiotherapy, hormones and oral tyrosine-kinase inhibitors (TKIs), with limited success. The predominant global standard-of-care after nephrectomy remains active monitoring. Immune checkpoint inhibitors (ICIs) are effective in the treatment of metastatic RCC; RAMPART will investigate these agents in the adjuvant setting. METHODS/DESIGN: RAMPART is an international, UK-led trial investigating the addition of ICIs after nephrectomy in patients with resected locally advanced RCC. RAMPART is a multi-arm multi-stage (MAMS) platform trial, upon which additional research questions may be addressed over time. The target population is patients with histologically proven resected locally advanced RCC (clear cell and non-clear cell histological subtypes), with no residual macroscopic disease, who are at high or intermediate risk of relapse (Leibovich score 3-11). Patients with fully resected synchronous ipsilateral adrenal metastases are included. Participants are randomly assigned (3,2:2) to Arm A - active monitoring (no placebo) for one year, Arm B - durvalumab (PD-L1 inhibitor) 4-weekly for one year; or Arm C - combination therapy with durvalumab 4-weekly for one year plus two doses of tremelimumab (CTLA-4 inhibitor) at day 1 of the first two 4-weekly cycles. The co-primary outcomes are disease-free-survival (DFS) and overall survival (OS). Secondary outcomes include safety, metastasis-free survival, RCC specific survival, quality of life, and patient and clinician preferences. Tumour tissue, plasma and urine are collected for molecular analysis (TransRAMPART). TRIAL REGISTRATION: ISRCTN #: ISRCTN53348826, NCT #: NCT03288532, EUDRACT #: 2017-002329-39, CTA #: 20363/0380/001-0001, MREC #: 17/LO/1875, ClinicalTrials.gov Identifier: NCT03288532, RAMPART grant number: MC_UU_12023/25, TransRAMPART grant number: A28690 Cancer Research UK, RAMPART Protocol version 5.0..
Meade, A.
Oza, B.
Frangou, E.
Smith, B.
Bryant, H.
Kaplan, R.
Choodari-Oskooei, B.
Powles, T.
Stewart, G.D.
Albiges, L.
Bex, A.
Choueiri, T.K.
Davis, I.D.
Eisen, T.
Fielding, A.
Harrison, D.J.
McWhirter, A.
Mulhere, S.
Nathan, P.
Rini, B.
Ritchie, A.
Scovell, S.
Shakeshaft, C.
Stockler, M.R.
Thorogood, N.
Larkin, J.
Parmar, M.K.
(2021). RAMPART: A model for a regulatory-ready academic-led phase III trial in the adjuvant renal cell carcinoma setting. ,
Vol.108,
p. 106481.
show abstract
The development of therapeutics in oncology is a highly active research area for the pharmaceutical and biotechnology industries, but also has a strong academic base. Many new agents have been developed in recent years, most with specific biological targets. This has mandated the need to look at different ways to streamline the evaluation of new agents. One solution has been the development of adaptive trial designs that allow the evaluation of multiple agents, concentrating on the most promising agents while screening out those which are unlikely to benefit patients. Another way forward has been the growth of partnerships between academia and industry with the shared goal of designing and conducting high quality clinical trials which answer important clinical questions as efficiently as possible. The RAMPART trial (NCT03288532) brings together both of these processes in an attempt to improve outcomes for patients with locally advanced renal cell carcinoma (RCC), where no globally acceptable adjuvant strategy after nephrectomy currently exist. RAMPART is led by the MRC CTU at University College London (UCL), in collaboration with other international academic groups and industry. We aim to facilitate the use of data from RAMPART, (dependent on outcomes), for a future regulatory submission that will extend the license of the agents being investigated. We share our experience in order to lay the foundations for an effective trial design and conduct framework and to guide others who may be considering similar collaborations. Trial Registration: ISRCTN #: ISRCTN53348826, NCT #: NCT03288532, EUDRACT #: 2017-002329-39. CTA #: 20363/0380/001-0001. MREC #: 17/LO/1875. ClinicalTrials.gov Identifier: NCT03288532 RAMPART grant number: MC_UU_12023/25. . RAMPART Protocol version 5.0..
Zhao, Y.
Fu, X.
Lopez, J.I.
Rowan, A.
Au, L.
Fendler, A.
Hazell, S.
Xu, H.
Horswell, S.
Shepherd, S.T.
Spain, L.
Byrne, F.
Stamp, G.
O'Brien, T.
Nicol, D.
Augustine, M.
Chandra, A.
Rudman, S.
Toncheva, A.
Pickering, L.
Sahai, E.
Larkin, J.
Bates, P.A.
Swanton, C.
Turajlic, S.
TRACERx Renal Consortium,
Litchfield, K.
(2021). Selection of metastasis competent subclones in the tumour interior. ,
Vol.5
(7),
pp. 1033-1045.
show abstract
The genetic evolutionary features of solid tumour growth are becoming increasingly well described, but the spatial and physical nature of subclonal growth remains unclear. Here, we utilize 102 macroscopic whole-tumour images from clear cell renal cell carcinoma patients, with matched genetic and phenotypic data from 756 biopsies. Utilizing a digital image processing pipeline, a renal pathologist marked the boundaries between tumour and normal tissue and extracted positions of boundary line and biopsy regions to X and Y coordinates. We then integrated coordinates with genomic data to map exact spatial subclone locations, revealing how genetically distinct subclones grow and evolve spatially. We observed a phenotype of advanced and more aggressive subclonal growth in the tumour centre, characterized by an elevated burden of somatic copy number alterations and higher necrosis, proliferation rate and Fuhrman grade. Moreover, we found that metastasizing subclones preferentially originate from the tumour centre. Collectively, these observations suggest a model of accelerated evolution in the tumour interior, with harsh hypoxic environmental conditions leading to a greater opportunity for driver somatic copy number alterations to arise and expand due to selective advantage. Tumour subclone growth is predominantly spatially contiguous in nature. We found only two cases of subclone dispersal, one of which was associated with metastasis. The largest subclones spatially were dominated by driver somatic copy number alterations, suggesting that a large selective advantage can be conferred to subclones upon acquisition of these alterations. In conclusion, spatial dynamics is strongly associated with genomic alterations and plays an important role in tumour evolution..
Eggermont, A.M.
Meshcheryakov, A.
Atkinson, V.
Blank, C.U.
Mandala, M.
Long, G.V.
Barrow, C.
Di Giacomo, A.M.
Fisher, R.
Sandhu, S.
Kudchadkar, R.
Ortiz Romero, P.L.
Svane, I.M.
Larkin, J.
Puig, S.
Hersey, P.
Quaglino, P.
Queirolo, P.
Stroyakovskiy, D.
Bastholt, L.
Mohr, P.
Hernberg, M.
Chiarion-Sileni, V.
Strother, M.
Hauschild, A.
Yamazaki, N.
van Akkooi, A.C.
Lorigan, P.
Krepler, C.
Ibrahim, N.
Marreaud, S.
Kicinski, M.
Suciu, S.
Robert, C.
(2021). Crossover and rechallenge with pembrolizumab in recurrent patients from the EORTC 1325-MG/Keynote-054 phase III trial, pembrolizumab versus placebo after complete resection of high-risk stage III melanoma. ,
Vol.158,
pp. 156-168.
show abstract
BACKGROUND: In the phase III double-blind European Organisation for Research and Treatment of Cancer 1325/KEYNOTE-054 trial, pembrolizumab improved recurrence-free and distant metastasis-free survival in patients with stage III cutaneous melanoma with complete resection of lymph nodes. In the pembrolizumab group, the incidence of grade I-V and of grade III-V immune-related adverse events (irAEs) was 37% and 7%, respectively. METHODS: Patients were randomised to receive intravenous (i.v.) pembrolizumab 200 mg (N = 514) or placebo (N = 505) every 3 weeks, up to 1 year. On recurrence, patients could enter part 2 of the study: pembrolizumab 200 mg i.v. every 3 weeks up to 2 years, for crossover (those who received placebo) or rechallenge (those who had recurrence ≥6 months after completing 1-year adjuvant pembrolizumab therapy). For these patients, we present the safety profile and efficacy outcomes. RESULTS: At the clinical cut-off (16-Oct-2020), in the placebo group, 298 patients had a disease recurrence, in which 155 (52%) crossed over ('crossover'). In the pembrolizumab group, 297 patients completed the 1-year treatment period; 47 had a recurrence ≥6 months later, in which 20 (43%) entered the rechallenge part 2 ('rechallenge'). In the crossover group, the median progression-free survival (PFS) was 8.5 months (95% confidence interval [CI] 5.7-15.2) and the 3-year PFS rate was 32% (95% CI 25-40%). Among 80 patients with stage IV evaluable disease, 31 (39%) had an objective response: 14 (18%) patients with complete response (CR) and 17 (21%) patients with partial response. The 2-year PFS rate from response was 69% (95% CI 48-83%). In the rechallenge group, the median PFS was 4.1 months (95% CI 2.6-NE). Among 9 patients with stage IV evaluable disease, 1 had an objective response (CR). Among the 175 patients, 51 (29%) had a grade I-IV irAE and 11 (6%) had a grade III-IV irAE. CONCLUSIONS: Pembrolizumab treatment after crossover yielded an overall 3-year PFS rate of 32% and a 39% ORR in evaluable patients, but the efficacy (11% ORR) was lower in those rechallenged..
McDermott, D.F.
Lee, J.-.
Bjarnason, G.A.
Larkin, J.M.
Gafanov, R.A.
Kochenderfer, M.D.
Jensen, N.V.
Donskov, F.
Malik, J.
Poprach, A.
Tykodi, S.S.
Alonso-Gordoa, T.
Cho, D.C.
Geertsen, P.F.
Climent Duran, M.A.
DiSimone, C.
Silverman, R.K.
Perini, R.F.
Schloss, C.
Atkins, M.B.
(2021). Open-Label, Single-Arm Phase II Study of Pembrolizumab Monotherapy as First-Line Therapy in Patients With Advanced Clear Cell Renal Cell Carcinoma. ,
Vol.39
(9),
pp. 1020-1028.
show abstract
PURPOSE: Pembrolizumab, a programmed death 1 inhibitor, demonstrated promising single-agent activity in untreated patients with various cancer types. The phase II KEYNOTE-427 study evaluated efficacy and safety of single-agent pembrolizumab in treatment-naive patients with advanced clear cell renal cell carcinoma (ccRCC; cohort A) and advanced non-ccRCC (cohort B). Results of cohort A are reported. METHODS: In this open-label, single-arm phase II study, patients with advanced ccRCC received pembrolizumab 200 mg every 3 weeks for ≤ 24 months. The primary end point was objective response rate by RECIST, version 1.1. RESULTS: In the total population (N = 110), median time from enrollment to data cutoff was 35.9 (range, 29.5-40.3) months. Objective response rate was 36.4% with four (3.6%) complete responses and 36 (32.7%) partial responses; disease control rate was 58.2% (95% CI, 48.4 to 67.5). Most patients (68.2%) had a decrease in target lesions, including 30.9% with a reduction ≥ 60%. Median duration of response was 18.9 (range, 2.3-37.6+) months; 64.1% of responders had a response ≥ 12 months (Kaplan-Meier). Median progression-free survival was 7.1 months (95% CI, 5.6 to 11.0). Median overall survival was not reached; 12-month and 24-month overall survival rates were 88.2% and 70.8%, respectively. Durable responses were observed across all International Metastatic RCC Database Consortium categories. Grade 3-5 treatment-related adverse events were reported in 30.0% of patients, of which colitis and diarrhea were most frequent. CONCLUSION: Single-agent pembrolizumab showed promising antitumor activity as a first-line treatment in patients with advanced ccRCC, with durable responses across International Metastatic RCC Database Consortium categories. Safety and tolerability profile of pembrolizumab monotherapy was comparable to what has been previously described in other tumor types..
Choueiri, T.K.
Larkin, J.
Pal, S.
Motzer, R.J.
Rini, B.I.
Venugopal, B.
Alekseev, B.
Miyake, H.
Gravis, G.
Bilen, M.A.
Hariharan, S.
Chudnovsky, A.
Ching, K.A.
Mu, X.J.
Mariani, M.
Robbins, P.B.
Huang, B.
di Pietro, A.
Albiges, L.
(2021). Efficacy and correlative analyses of avelumab plus axitinib versus sunitinib in sarcomatoid renal cell carcinoma: post hoc analysis of a randomized clinical trial. ,
Vol.6
(3),
p. 100101.
show abstract
BACKGROUND: Among patients with advanced renal cell carcinoma (RCC), those with sarcomatoid histology (sRCC) have the poorest prognosis. This analysis assessed the efficacy of avelumab plus axitinib versus sunitinib in patients with treatment-naive advanced sRCC. METHODS: The randomized, open-label, multicenter, phase III JAVELIN Renal 101 trial (NCT02684006) enrolled patients with treatment-naive advanced RCC. Patients were randomized 1 : 1 to receive either avelumab plus axitinib or sunitinib following standard doses and schedules. Assessments in this post hoc analysis of patients with sRCC included efficacy (including progression-free survival) and biomarker analyses. RESULTS: A total of 108 patients had sarcomatoid histology and were included in this post hoc analysis; 47 patients in the avelumab plus axitinib arm and 61 in the sunitinib arm. Patients in the avelumab plus axitinib arm had improved progression-free survival [stratified hazard ratio, 0.57 (95% confidence interval, 0.325-1.003)] and a higher objective response rate (46.8% versus 21.3%; complete response in 4.3% versus 0%) versus those in the sunitinib arm. Correlative gene expression analyses of patients with sRCC showed enrichment of gene pathway scores for cancer-associated fibroblasts and regulatory T cells, CD274 and CD8A expression, and tumors with The Cancer Genome Atlas m3 classification. CONCLUSIONS: In this subgroup analysis of JAVELIN Renal 101, patients with sRCC in the avelumab plus axitinib arm had improved efficacy outcomes versus those in the sunitinib arm. Correlative analyses provide insight into this subtype of RCC and suggest that avelumab plus axitinib may increase the chance of overcoming the aggressive features of sRCC..
Au, L.
Fendler, A.
Shepherd, S.T.
Rzeniewicz, K.
Cerrone, M.
Byrne, F.
Carlyle, E.
Edmonds, K.
Del Rosario, L.
Shon, J.
Haynes, W.A.
Ward, B.
Shum, B.
Gordon, W.
Gerard, C.L.
Xie, W.
Joharatnam-Hogan, N.
Young, K.
Pickering, L.
Furness, A.J.
Larkin, J.
Harvey, R.
Kassiotis, G.
Gandhi, S.
Crick COVID-19 Consortium,
Swanton, C.
Fribbens, C.
Wilkinson, K.A.
Wilkinson, R.J.
Lau, D.K.
Banerjee, S.
Starling, N.
Chau, I.
CAPTURE Consortium,
Turajlic, S.
(2021). Cytokine release syndrome in a patient with colorectal cancer after vaccination with BNT162b2. Nature medicine,
.
show abstract
Patients with cancer are currently prioritized in coronavirus disease 2019 (COVID-19) vaccination programs globally, which includes administration of mRNA vaccines. Cytokine release syndrome (CRS) has not been reported with mRNA vaccines and is an extremely rare immune-related adverse event of immune checkpoint inhibitors. We present a case of CRS that occurred 5 d after vaccination with BTN162b2 (tozinameran)-the Pfizer-BioNTech mRNA COVID-19 vaccine-in a patient with colorectal cancer on long-standing anti-PD-1 monotherapy. The CRS was evidenced by raised inflammatory markers, thrombocytopenia, elevated cytokine levels (IFN-γ/IL-2R/IL-18/IL-16/IL-10) and steroid responsiveness. The close temporal association of vaccination and diagnosis of CRS in this case suggests that CRS was a vaccine-related adverse event; with anti-PD1 blockade as a potential contributor. Overall, further prospective pharmacovigillence data are needed in patients with cancer, but the benefit-risk profile remains strongly in favor of COVID-19 vaccination in this population..
Fendler, A.
Shepherd, S.T.
Au, L.
Wilkinson, K.A.
Wu, M.
Byrne, F.
Cerrone, M.
Schmitt, A.M.
Joharatnam-Hogan, N.
Shum, B.
Tippu, Z.
Rzeniewicz, K.
Boos, L.A.
Harvey, R.
Carlyle, E.
Edmonds, K.
Del Rosario, L.
Sarker, S.
Lingard, K.
Mangwende, M.
Holt, L.
Ahmod, H.
Korteweg, J.
Foley, T.
Bazin, J.
Gordon, W.
Barber, T.
Emslie-Henry, A.
Xie, W.
Gerard, C.L.
Deng, D.
Wall, E.C.
Agua-Doce, A.
Namjou, S.
Caidan, S.
Gavrielides, M.
MacRae, J.
Kelly, G.
Peat, K.
Kelly, D.
Murra, A.
Kelly, K.
O'Flaherty, M.
Dowdie, L.
Ash, N.
Gronthoud, F.
Shea, R.L.
Gardner, G.
Murray, D.
Kinnaird, F.
Cui, W.
Pascual, J.
Rodney, S.
Mencel, J.
Curtis, O.
Stephenson, C.
Robinson, A.
Oza, B.
Farag, S.
Leslie, I.
Rogiers, A.
Iyengar, S.
Ethell, M.
Messiou, C.
Cunningham, D.
Chau, I.
Starling, N.
Turner, N.
Welsh, L.
van As, N.
Jones, R.L.
Droney, J.
Banerjee, S.
Tatham, K.C.
O'Brien, M.
Harrington, K.
Bhide, S.
Okines, A.
Reid, A.
Young, K.
Furness, A.J.
Pickering, L.
Swanton, C.
Gandhi, S.
Gamblin, S.
Bauer, D.L.
Kassiotis, G.
Kumar, S.
Yousaf, N.
Jhanji, S.
Nicholson, E.
Howell, M.
Walker, S.
Wilkinson, R.J.
Larkin, J.
Turajlic, S.
(2021). Adaptive immunity and neutralizing antibodies against SARS-CoV-2 variants of concern following vaccination in patients with cancer: the CAPTURE study. Nature cancer,
,
pp. ?-? (31).
Scherrer, E.
Rau, R.
Lorenzi, M.
Shui, I.
Townson, S.
Larkin, J.
(2021). Systematic literature review for the association of biomarkers with efficacy of anti-PD-1 inhibitors in advanced melanoma. ,
Vol.17
(20),
pp. 2683-2692.
show abstract
Aim: Summarize the literature assessing biomarkers in predicting efficacy of anti-PD-1 therapy for patients with high-risk unresectable or metastatic melanoma. Materials & methods: Relevant studies were identified via a systematic literature review. Results: About 334 unique biomarkers or biomarker combinations were identified from 121 citations. Neutrophil-to-lymphocyte ratio was the most frequently studied biomarker, followed by C-reactive protein. Fifty-nine biomarkers were significantly associated with overall survival (OS), 51 with progression-free survival (PFS) and 44 with response. Twenty biomarkers were associated with both OS and PFS; two were associated with OS, PFS and response (MHC-II and tumor mutational burden). Conclusion: Numerous biomarkers could potentially predict the efficacy of anti-PD-1-based therapy for melanoma patients. However, confirmatory studies are needed as well as determination of implications for clinical decision-making..
Piperno-Neumann, S.
Larkin, J.
Carvajal, R.D.
Luke, J.J.
Schwartz, G.K.
Hodi, F.S.
Sablin, M.-.
Shoushtari, A.N.
Szpakowski, S.
Chowdhury, N.R.
Brannon, A.R.
Ramkumar, T.
de Koning, L.
Derti, A.
Emery, C.
Yerramilli-Rao, P.
Kapiteijn, E.
(2020). Genomic Profiling of Metastatic Uveal Melanoma and Clinical Results of a Phase I Study of the Protein Kinase C Inhibitor AEB071. Molecular cancer therapeutics,
Vol.19
(4),
pp. 1031-1039.
show abstract
Abstract
Up to 50% of patients with uveal melanoma (UM) develop metastatic disease, for which there is no effective systemic treatment. This study aimed to evaluate the safety and efficacy of the orally available protein kinase C inhibitor, AEB071, in patients with metastatic UM, and to perform genomic profiling of metastatic tumor samples, with the aim to propose combination therapies. Patients with metastatic UM (n = 153) were treated with AEB071 in a phase I, single-arm study. Patients received total daily doses of AEB071 ranging from 450 to 1,400 mg. First-cycle dose-limiting toxicities were observed in 13 patients (13%). These were most commonly gastrointestinal system toxicities and were dose related, occurring at doses ≥700 mg/day. Preliminary clinical activity was observed, with 3% of patients achieving a partial response and 50% with stable disease (median duration 15 weeks). High-depth, targeted next-generation DNA sequencing was performed on 89 metastatic tumor biopsy samples. Mutations previously identified in UM were observed, including mutations in GNAQ, GNA11, BAP1, SF3B1, PLCB4, and amplification of chromosome arm 8q. GNAQ/GNA11 mutations were observed at a similar frequency (93%) as previously reported, confirming a therapeutic window for inhibition of the downstream effector PKC in metastatic UM.
In conclusion, the protein kinase C inhibitor AEB071 was well tolerated, and modest clinical activity was observed in metastatic UM. The genomic findings were consistent with previous reports in primary UM. Together, our data allow envisaging combination therapies of protein kinase C inhibitors with other compounds in metastatic UM.
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Eggermont, A.M.
Kicinski, M.
Blank, C.U.
Mandala, M.
Long, G.V.
Atkinson, V.
Dalle, S.
Haydon, A.
Khattak, A.
Carlino, M.S.
Sandhu, S.
Larkin, J.
Puig, S.
Ascierto, P.A.
Rutkowski, P.
Schadendorf, D.
Koornstra, R.
Hernandez-Aya, L.
Di Giacomo, A.M.
van den Eertwegh, A.J.
Grob, J.-.
Gutzmer, R.
Jamal, R.
Lorigan, P.C.
Krepler, C.
Ibrahim, N.
Marreaud, S.
van Akkooi, A.
Robert, C.
Suciu, S.
(2020). Association Between Immune-Related Adverse Events and Recurrence-Free Survival Among Patients With Stage III Melanoma Randomized to Receive Pembrolizumab or Placebo: A Secondary Analysis of a Randomized Clinical Trial. ,
Vol.6
(4),
pp. 519-527.
show abstract
Importance: Whether immune-related adverse events (irAEs) indicate drug activity in patients treated with immune checkpoint inhibitors remains unknown. Objective: To investigate the association between irAEs and recurrence-free survival (RFS) in the double-blind EORTC 1325/KEYNOTE-054 clinical trial comparing pembrolizumab therapy and placebo for the treatment of patients with high-risk stage III melanoma. Design, Setting, and Participants: A total of 1019 adults with stage III melanoma were randomly assigned on a 1:1 ratio to receive treatment with pembrolizumab therapy or placebo. Eligible patients were adults 18 years and older with complete resection of cutaneous melanoma metastatic to lymph nodes, classified with stage IIIA (at least 1 micrometastasis measuring >1 mm in greatest diameter), IIIB, or IIIC (without in-transit metastasis) cancer. Patients were randomized from August 26, 2015, to November 14, 2016. The clinical cutoff for the data set was October 2, 2017. Analyses were then performed on the database, which was locked on November 28, 2017. Interventions: Participants were scheduled to receive 200 mg of pembrolizumab or placebo every 3 weeks for a total of 18 doses for approximately 1 year or until disease recurrence, unacceptable toxic effects, major protocol violation, or withdrawal of consent. Main Outcomes and Measures: The association between irAEs and RFS was estimated using a Cox model adjusted for sex, age, and AJCC-7 stage, with a time-varying covariate that had a value of 0 before irAE onset and 1 after irAE onset. Results: Of 1011 patients who began treatment with pembrolizumab therapy or placebo, 622 (61.5%) were men and 389 (38.5%) were women; 386 patients (38.2%) were aged 50 to 64 years, 377 (37.3%) were younger than 50 years, and 248 (24.5%) were 65 years and older. Consistent with the reported main analysis in the intent-to-treat population, RFS was longer in the pembrolizumab arm compared with the placebo arm (hazard ratio [HR], 0.56; 98.4% CI, 0.43-0.74) among patients who started treatment. The incidence of irAEs was 190 (37.4%) in the pembrolizumab arm (n = 509) and 45 (9.0%) in the placebo arm (n = 502); in each treatment group, the incidence was similar for men and women. The occurrence of an irAE was associated with a longer RFS in the pembrolizumab arm (HR, 0.61; 95% CI, 0.39-0.95; P = .03) in both men and women. However, in the placebo arm, this association was not significant. Compared with the placebo arm, the reduction in the hazard of recurrence or death in the pembrolizumab arm was greater after the onset of an irAE than without or before an irAE (HR, 0.37; 95% CI, 0.24-0.57 vs HR, 0.61; 95% CI, 0.49-0.77, respectively; P = .03). Conclusions and Relevance: In this study, the occurrence of an irAE was associated with a longer RFS in the pembrolizumab arm. Trial Registrations: ClinicalTrials.gov identifier: NCT02362594; EudraCT identifier: 2014-004944-37..
Peach, H.
Board, R.
Cook, M.
Corrie, P.
Ellis, S.
Geh, J.
King, P.
Laitung, G.
Larkin, J.
Marsden, J.
Middleton, M.
Moncrieff, M.
Nathan, P.
Powell, B.
Pritchard-Jones, R.
Rodwell, S.
Steven, N.
Lorigan, P.
(2020). Current role of sentinel lymph node biopsy in the management of cutaneous melanoma: A UK consensus statement. Journal of plastic, reconstructive & aesthetic surgery,
Vol.73
(1),
pp. 36-42.
Haanen, J.
Ernstoff, M.
Wang, Y.
Menzies, A.
Puzanov, I.
Grivas, P.
Larkin, J.
Peters, S.
Thompson, J.
Obeid, M.
(2020). Rechallenge patients with immune checkpoint inhibitors following severe immune-related adverse events: review of the literature and suggested prophylactic strategy. ,
Vol.8
(1),
p. e000604.
show abstract
Patients with cancer who developed severe, grade 3 or 4 immune-related adverse events (irAEs) during therapy with immune checkpoint inhibitors are at risk for developing severe toxicities again on rechallenge with checkpoint inhibitors. Consequently, medical oncologists and multidisciplinary teams are hesitant to retreat in this scenario, despite the fact that a number of patients may derive clinical benefit from this approach. Balancing such clinical benefit and treatment-related toxicities for each patient is becoming increasingly challenging as more and more patients with cancer are being treated with checkpoint inhibitors. In this manuscript, we provide an extensive overview of the relevant literature on retreatment after toxicity, and suggest prophylactic approaches to minimize the risk of severe irAE following rechallenge with immune checkpoint blockade, since treatment may be lifesaving in a number of occasions..
Powell, N.
Ibraheim, H.
Raine, T.
Speight, R.A.
Papa, S.
Brain, O.
Green, M.
Samaan, M.A.
Spain, L.
Yousaf, N.
Hunter, N.
Eldridge, L.
Pavlidis, P.
Irving, P.
Hayee, B.
Turajlic, S.
Larkin, J.
Lindsay, J.O.
Gore, M.
(2020). British Society of Gastroenterology endorsed guidance for the management of immune checkpoint inhibitor-induced enterocolitis. ,
Vol.5
(7),
pp. 679-697.
show abstract
Immune checkpoint inhibitors are a novel class of cancer treatment that have improved outcomes for a subset of cancer patients. They work by antagonising inhibitory immune pathways, thereby augmenting immune-mediated antitumour responses. However, immune activation is not cancer-specific and often results in the activation of immune cells in non-cancer tissues, resulting in off-target immune-mediated injury and organ dysfunction. Diarrhoea and gastrointestinal tract inflammation are common and sometimes serious side-effects of this type of therapy. Prompt recognition of gastrointestinal toxicity and, in many cases, rapid institution of anti-inflammatory or biologic therapy (or both) is required to reverse these complications. Management of organ-specific complications benefits from multidisciplinary input, including engagement with gastroenterologists for optimal management of immune checkpoint inhibitor-induced enterocolitis. In this British Society of Gastroenterology endorsed guidance document, we have developed a consensus framework for the investigation and management of immune checkpoint inhibitor-induced enterocolitis..
Schmidinger, M.
Porta, C.
Oudard, S.
Denechere, G.
Brault, Y.
Serfass, L.
Costa, N.
Larkin, J.
(2020). Real-world Experience With Sunitinib Treatment in Patients With Metastatic Renal Cell Carcinoma: Clinical Outcome According to Risk Score. ,
Vol.18
(5),
pp. e588-e597.
show abstract
BACKGROUND: ADONIS is an ongoing observational study in 9 European countries, designed to evaluate treatment patterns/outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with first-line sunitinib and/or second-line axitinib post sunitinib. We present an evaluation of sunitinib efficacy by risk group, in the real-world setting examined in ADONIS. PATIENTS AND METHODS: Patients were enrolled at the start of first-line sunitinib treatment or second-line axitinib post sunitinib treatment. Evaluation of sunitinib efficacy was assessed by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) and Memorial Sloan Kettering Cancer Center risk criteria. RESULTS: For all patients in this analysis (N = 467), the median progression-free survival was 23.8 months (95% confidence interval [CI], 16.5-28.5 months), 11.8 months (95% CI, 8.1-17.4 months), and 4.6 months (95% CI, 2.5-7.7 months) for IMDC favorable-, intermediate-, and poor-risk groups, respectively. The median overall survival was 97.1 months (95% CI, 46.3 months-not evaluable [NE]), 33.5 months (95% CI, 20.5-46.6 months), and 10.0 months (95% CI, 4.5-19.8 months) for the respective risk groups. Data on individual risk factors were available for a subgroup of patients, allowing analysis by intermediate risk by 1 versus 2 risk factors. When including this subgroup (n = 120), the median overall survival for IMDC favorable-, intermediate-1, and intermediate-2 risk factors was 21.6 months (95% CI, 16.3 months-NE), 20.5 months (15.5 months-NE), and 15.1 months (4.1 months-NE), respectively. CONCLUSIONS: For patients overall and by risk-group stratification, survival estimates were aligned with previously published data. In patients with intermediate-1 risk, overall survival was very similar to patients with favorable risk. However, further exploration of outcome data from different sources is needed to confirm these observations..
Aeppli, S.
Eboulet, E.I.
Eisen, T.
Escudier, B.
Fischer, S.
Larkin, J.
Gruenwald, V.
McDermott, D.
Oldenburg, J.
Omlin, A.
Porta, C.
Rini, B.
Schmidinger, M.
Sternberg, C.
Rothermundt, C.
(2020). Impact of COVID-19 pandemic on treatment patterns in metastatic clear cell renal cell carcinoma. ,
Vol.5
(Suppl 3),
p. e000852.
show abstract
BACKGROUND: The coronavirus pandemic has provoked discussions among healthcare providers how to manage cancer patients when faced with the threat of severe acute respiratory syndrome related coronavirus 2 (SARS-CoV-2) infection. Immune checkpoint inhibitor (ICI) containing regimens are standard of care in the majority of metastatic clear cell renal cell carcinoma (mccRCC) patients. It remains unclear whether therapies should be modified in response to the COVID-19 pandemic. METHODS: We performed an online survey among physicians involved in the treatment of mccRCC, and 41 experts responded. Questions focused on criteria relevant for treatment decision outside the pandemic and the modifications of systemic therapy during COVID-19. FINDINGS: For the majority of experts (73%), the combination of International metastatic renal cell carcinoma Database Consortium (IMDC) risk category and patient fitness are two important factors for decision-making. The main treatment choice in fit, favourable risk patients outside the pandemic is pembrolizumab/axitinib for 53%, avelumab/axitinib, sunitinib or pazopanib for 13% of experts each. During the pandemic, ICI-containing regimens are chosen less often in favour of a tyrosine kinase inhibitors (TKI) monotherapy, mainly sunitinib or pazopanib (35%).In fit, intermediate/poor-risk patients outside the pandemic, over 80% of experts choose ipilimumab/nivolumab, in contrast to only 41% of physicians during COVID-19, instead more TKI monotherapies are given. In patients responding to established therapies with ICI/ICI or ICI/TKI combinations, most participants modify treatment regimen by extending cycle length, holding one ICI or even both. CONCLUSION: mccRCC treatment modifications in light of the coronavirus pandemic are variable, with a shift from ICI/ICI to ICI/TKI or TKI monotherapy..
Favara, D.M.
Spain, L.
Au, L.
Clark, J.
Daniels, E.
Diem, S.
Chauhan, D.
Turajlic, S.
Powell, N.
Larkin, J.M.
Yousaf, N.
(2020). Five-year review of corticosteroid duration and complications in the management of immune checkpoint inhibitor-related diarrhoea and colitis in advanced melanoma. ,
Vol.5
(4),
p. e000585.
show abstract
BACKGROUND: Immune-related diarrhoea/colitis (ir-D/C) is a common adverse event of immune checkpoint inhibitor (ICI) therapy. Guidelines recommend corticosteroid (CS) treatment; however, the average treatment duration for ir-D/C remains poorly defined. METHODS: All advanced melanoma patients treated with ICI therapy at the Royal Marsden Hospital between 2011 and 2016 were reviewed to identify ir-D/C cases alongside clinical variables. RESULTS: 117 any-grade ir-D/C episodes occurred in 109 (21%) patients out of a total of 519 patients treated (ipilimumab=77 episodes, anti-PD1=17 (nivolumab or pembrolizumab), ipilimumab and nivolumab=23 (ipi+nivo)) (seven patients had ir-D/C more than once on different lines of treatment) and >/=grade 3 ir-D/C occurred most frequently (63/519 patients (12%) vs 29/519 (5%) grade 1, and 25/519 (5%) grade 2). Median onset (days) of all-grade ir-D/C after starting ICI therapy was 41 for ipilimumab (IQR 24 to 59, n=77), 91 for anti-PD1 (IQR 46 to 355, n=17) and 45 for ipi+nivo (IQR 24 to 67, n=23). In 71/117 (61%) patients, ir-D/C episodes were treated with CS (17% grade 2; 79% grade 3/4): 54 being steroid-responsive; 17 being steroid-refractory and received additional anti-tumor necrosis factor (TNF) treatment. Median grade 3 ir-D/C CS duration was similar across treatments, averaging 58 days. Median overall CS duration (days) was longer in the grade 3/4 D/C steroid-refractory group (94 vs 45 days). Infection developed in 11/71 (15%) CS recipients and in 6/17 (35%) anti-TNF recipients. In 65/117 (55%) patients, ir-D/C episodes were investigated with flexible sigmoidoscopy. Of these patients, 38/65 (58%) had macroscopic colitis and 12/65 (18%) had microscopic colitis. The steroid-refractory group had more macroscopic changes, 13/17 (76%), than the steroid-responsive group, 22/41 (54%). CONCLUSION: Rates of grade 3 ir-D/C were higher than reported in clinical trials. The 58-day median duration of CS therapy for grade 3 ir-D/C places a significant number of patients at risk of complications. We demonstrate that microscopic colitis is an important subgroup, advocating biopsies in ir-D/C even with macroscopically normal bowel..
Eisen, T.
Frangou, E.
Oza, B.
Ritchie, A.W.
Smith, B.
Kaplan, R.
Davis, I.D.
Stockler, M.R.
Albiges, L.
Escudier, B.
Larkin, J.
Bex, A.
Joniau, S.
Hancock, B.
Hermann, G.G.
Bellmunt, J.
Hodgkinson, E.
Stewart, G.D.
Barber, J.
Brown, J.
McMenemin, R.
Nathan, P.
Pickering, L.M.
Parmar, M.K.
Meade, A.
(2020). Adjuvant Sorafenib for Renal Cell Carcinoma at Intermediate or High Risk of Relapse: Results From the SORCE Randomized Phase III Intergroup Trial. J clin oncol,
Vol.38
(34),
pp. 4064-4075.
show abstract
PURPOSE: SORCE is an international, randomized, double-blind, three-arm trial of sorafenib after surgical excision of primary renal cell carcinoma (RCC) found to be at intermediate or high risk of recurrence. PATIENTS AND METHODS: We randomly assigned participants (2:3:3) to 3 years of placebo (arm A), 1 year of sorafenib followed by 2 years of placebo (arm B), or 3 years of sorafenib (arm C). The initial sorafenib dose was 400 mg twice per day orally, amended to 400 mg daily. The primary outcome analysis, which was revised as a result of external results, was investigator-reported disease-free survival (DFS) comparing 3 years of sorafenib versus placebo. RESULTS: Between July 2007 and April 2013, we randomly assigned 1,711 participants (430, 642, and 639 participants in arms A, B, and C, respectively). Median age was 58 years, 71% of patients were men, 84% had clear cell histology, 53% were at intermediate risk of recurrence, and 47% were at high risk of recurrence. We observed no differences in DFS or overall survival in all randomly assigned patients, patients with high risk of recurrence, or patients with clear cell RCC only. Median DFS was not reached for 3 years of sorafenib or for placebo (hazard ratio, 1.01; 95% CI, 0.83 to 1.23; P = .95). We observed nonproportional hazards; the restricted mean survival time (RMST) was 6.81 years for 3 years of sorafenib and 6.82 years for placebo (RMST difference, 0.01 year; 95% CI, -0.49 to 0.48 year; P = .99). Despite offering treatment adaptations, more than half of participants stopped treatment by 12 months. Grade 3 hand-foot skin reaction was reported in 24% of participants on sorafenib. CONCLUSION: Sorafenib should not be used as adjuvant therapy for RCC. Active surveillance remains the standard of care for patients at intermediate or high risk of recurrence after nephrectomy and is the appropriate control of our current international adjuvant RCC trial, RAMPART..
Boos, L.A.
Leslie, I.
Larkin, J.
(2020). Metastatic melanoma: therapeutic agents in preclinical and early clinical development. Expert opinion on investigational drugs,
Vol.29
(7),
pp. 739-753.
O'Reilly, A.
Hughes, P.
Mann, J.
Lai, Z.
Teh, J.J.
Mclean, E.
Edmonds, K.
Lingard, K.
Chauhan, D.
Lynch, J.
Au, L.
Ludlow, A.
Pattison, N.
Wiseman, T.
Turajlic, S.
Gore, M.
Larkin, J.
Husson, O.
(2020). An immunotherapy survivor population: health-related quality of life and toxicity in patients with metastatic melanoma treated with immune checkpoint inhibitors. Supportive care in cancer : official journal of the multinational association of supportive care in cancer,
Vol.28
(2),
pp. 561-570.
show abstract
Purpose The immune checkpoint inhibitors (ICIs) have resulted in subgroups of patients with metastatic melanoma achieving high-quality durable responses. Metastatic melanoma survivors are a new population in the era of cancer survivorship. The aim of this study was to evaluate metastatic melanoma survivors in terms of health-related quality of life (HRQoL), immune-related adverse events (irAEs) and exposure to immunosuppressive agents in a large single centre in the UK.Methods We defined the survivor population as patients with a diagnosis of metastatic melanoma who achieved a durable response to an ICI and had been followed-up for a minimum of 12 months from initiation of ICI without disease progression. HRQoL was assessed using SF-36. Electronic health records were accessed to collect data on demographics, treatments, irAEs and survival. HRQoL data was compared with two norm-based datasets.Results Eighty-four metastatic melanoma survivors were eligible and 87% (N = 73) completed the SF-36. ICI-related toxicity of any grade occurred in 92% of patients and 43% had experienced a grade 3 or 4 toxicity. Almost half (49%) of the patients required steroids for the treatment of ICI-related toxicity, whilst 14% required treatment with an immunosuppressive agent beyond steroids. Melanoma survivors had statistically significant lower HRQoL scores with regard to physical, social and physical role functioning and general health compared with the normative population. There was a trend towards inferior scores in patients with previous exposure to ipilimumab compared with those never exposed to ipilimumab.Conclusions Our results show that metastatic melanoma survivors have potentially experienced significant ICI-related toxicity and experience significant impairments in specific HRQoL domains. Future service planning is required to meet this population's unique survivorship needs..
Ascierto, P.A.
Ribas, A.
Larkin, J.
McArthur, G.A.
Lewis, K.D.
Hauschild, A.
Flaherty, K.T.
McKenna, E.
Zhu, Q.
Mun, Y.
Dréno, B.
(2020). Impact of initial treatment and prognostic factors on postprogression survival in BRAF-mutated metastatic melanoma treated with dacarbazine or vemurafenib ± cobimetinib: a pooled analysis of four clinical trials. Journal of translational medicine,
Vol.18
(1),
pp. 294-?.
show abstract
Background We sought to identify patient subgroups with distinct postprogression overall survival (ppOS) outcomes and investigate the impact of original treatment assignment and initial postprogression treatment (ppRx) on ppOS.Methods Recursive partitioning analysis (RPA) was performed to model relationships between prespecified covariates and ppOS in patients with BRAF V600 -mutated metastatic melanoma who had experienced progressive disease (PD) following treatment with cobimetinib plus vemurafenib, vemurafenib monotherapy, or dacarbazine in the BRIM-2, BRIM-3, BRIM-7, and coBRIM studies. Prognostic subgroups identified by RPA were then applied to pooled treatment cohorts. The primary endpoint was ppOS, defined as time from first PD to death from any cause.Results RPA identified baseline lactate dehydrogenase (LDH), baseline disease stage, Eastern Cooperative Oncology Group performance status at PD, and ppRx as significant prognostic factors for ppOS. Median ppOS was longest in patients with normal baseline LDH, stage M1c disease at baseline, and ppRx with immunotherapy or targeted therapy (12.2 months; 95% CI 10.3-16.1) and shortest in those with elevated baseline LDH > 2 × upper limit of normal (2.3 months; 95% CI 1.8-2.7). Original treatment assignment did not impact ppOS. Across treatment cohorts, patients treated with immunotherapy or targeted therapy after PD had better ppOS than those given other treatments.Conclusion A combination of factors at baseline (LDH, disease stage) and PD (performance status, ppRx) impact ppOS outcomes. ppRx with immunotherapy or targeted therapy is an independent prognostic factor for improved overall survival following progression regardless of original treatment. Trial registration The trials included in this analysis are registered with ClinicalTrials.gov: NCT00949702 (BRIM-2), NCT01006980 (BRIM-3), NCT01271803 (BRIM-7), and NCT01689519 (coBRIM)..
Leslie, I.
Boos, L.A.
Larkin, J.
Pickering, L.
(2020). Avelumab and axitinib in the treatment of renal cell carcinoma: safety and efficacy. Expert review of anticancer therapy,
Vol.20
(5),
pp. 343-354.
Dummer, R.
Brase, J.C.
Garrett, J.
Campbell, C.D.
Gasal, E.
Squires, M.
Gusenleitner, D.
Santinami, M.
Atkinson, V.
Mandalà, M.
Chiarion-Sileni, V.
Flaherty, K.
Larkin, J.
Robert, C.
Kefford, R.
Kirkwood, J.M.
Hauschild, A.
Schadendorf, D.
Long, G.V.
(2020). Adjuvant dabrafenib plus trametinib versus placebo in patients with resected, BRAFV600-mutant, stage III melanoma (COMBI-AD): exploratory biomarker analyses from a randomised, phase 3 trial. The lancet oncology,
Vol.21
(3),
pp. 358-372.
Litchfield, K.
Stanislaw, S.
Spain, L.
Gallegos, L.L.
Rowan, A.
Schnidrig, D.
Rosenbaum, H.
Harle, A.
Au, L.
Hill, S.M.
Tippu, Z.
Thomas, J.
Thompson, L.
Xu, H.
Horswell, S.
Barhoumi, A.
Jones, C.
Leith, K.F.
Burgess, D.L.
Watkins, T.B.
Lim, E.
Birkbak, N.J.
Lamy, P.
Nordentoft, I.
Dyrskjøt, L.
Pickering, L.
Hazell, S.
Jamal-Hanjani, M.
PEACE Consortium,
Larkin, J.
Swanton, C.
Alexander, N.R.
Turajlic, S.
(2020). Representative Sequencing: Unbiased Sampling of Solid Tumor Tissue. ,
Vol.31
(5),
p. 107550.
show abstract
Although thousands of solid tumors have been sequenced to date, a fundamental under-sampling bias is inherent in current methodologies. This is caused by a tissue sample input of fixed dimensions (e.g., 6 mm biopsy), which becomes grossly under-powered as tumor volume scales. Here, we demonstrate representative sequencing (Rep-Seq) as a new method to achieve unbiased tumor tissue sampling. Rep-Seq uses fixed residual tumor material, which is homogenized and subjected to next-generation sequencing. Analysis of intratumor tumor mutation burden (TMB) variability shows a high level of misclassification using current single-biopsy methods, with 20% of lung and 52% of bladder tumors having at least one biopsy with high TMB but low clonal TMB overall. Misclassification rates by contrast are reduced to 2% (lung) and 4% (bladder) when a more representative sampling methodology is used. Rep-Seq offers an improved sampling protocol for tumor profiling, with significant potential for improved clinical utility and more accurate deconvolution of clonal structure..
Ugurel, S.
Röhmel, J.
Ascierto, P.A.
Becker, J.C.
Flaherty, K.T.
Grob, J.J.
Hauschild, A.
Larkin, J.
Livingstone, E.
Long, G.V.
Lorigan, P.
McArthur, G.A.
Ribas, A.
Robert, C.
Zimmer, L.
Schadendorf, D.
Garbe, C.
(2020). Survival of patients with advanced metastatic melanoma: The impact of MAP kinase pathway inhibition and immune checkpoint inhibition - Update 2019. European journal of cancer,
Vol.130,
pp. 126-138.
Haanen, J.
Ernstoff, M.S.
Wang, Y.
Menzies, A.M.
Puzanov, I.
Grivas, P.
Larkin, J.
Peters, S.
Thompson, J.A.
Obeid, M.
(2020). Autoimmune diseases and immune-checkpoint inhibitors for cancer therapy: review of the literature and personalized risk-based prevention strategy. Annals of oncology,
Vol.31
(6),
pp. 724-744.
Maio, M.
Hamid, O.
Larkin, J.
Covre, A.
Altomonte, M.
Calabrò, L.
Vardhana, S.A.
Robert, C.
Ibrahim, R.
Anichini, A.
Wolchok, J.D.
Giacomo, A.M.
(2020). Immune Checkpoint Inhibitors for Cancer Therapy in the COVID-19 Era. Clinical cancer research : an official journal of the american association for cancer research,
Vol.26
(16),
pp. 4201-4205.
show abstract
The potential immune intersection between COVID-19 disease and cancer therapy raises important practical clinical questions and highlights multiple scientific gaps to be filled. Among available therapeutic approaches to be considered, immune checkpoint inhibitors (ICI) seem to require major attention as they may act at the crossroads between cancer treatment and COVID-19 disease, due to their profound immunomodulatory activity. On the basis of available literature evidence, we suggest guidance to consider for treating physicians, and propose areas of clinical and preclinical investigation. Comprehensively, although with the necessary caution, ICI therapy seems to remain a suitable therapeutic option for patients with cancer during the COVID-19 pandemic..
Choueiri, T.K.
Motzer, R.J.
Rini, B.I.
Haanen, J.
Campbell, M.T.
Venugopal, B.
Kollmannsberger, C.
Gravis-Mescam, G.
Uemura, M.
Lee, J.L.
Grimm, M.-.
Gurney, H.
Schmidinger, M.
Larkin, J.
Atkins, M.B.
Pal, S.K.
Wang, J.
Mariani, M.
Krishnaswami, S.
Cislo, P.
Chudnovsky, A.
Fowst, C.
Huang, B.
di Pietro, A.
Albiges, L.
(2020). Updated efficacy results from the JAVELIN Renal 101 trial: first-line avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma. Annals of oncology : official journal of the european society for medical oncology,
Vol.31
(8),
pp. 1030-1039.
show abstract
Background The phase 3 JAVELIN Renal 101 trial (NCT02684006) demonstrated significantly improved progression-free survival (PFS) with first-line avelumab plus axitinib versus sunitinib in advanced renal cell carcinoma (aRCC). We report updated efficacy data from the second interim analysis.Patients and methods Treatment-naive patients with aRCC were randomized (1 : 1) to receive avelumab (10 mg/kg) intravenously every 2 weeks plus axitinib (5 mg) orally twice daily or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The two independent primary end points were PFS and overall survival (OS) among patients with programmed death ligand 1-positive (PD-L1+) tumors. Key secondary end points were OS and PFS in the overall population.Results Of 886 patients, 442 were randomized to the avelumab plus axitinib arm and 444 to the sunitinib arm; 270 and 290 had PD-L1+ tumors, respectively. After a minimum follow-up of 13 months (data cut-off 28 January 2019), PFS was significantly longer in the avelumab plus axitinib arm than in the sunitinib arm {PD-L1+ population: hazard ratio (HR) 0.62 [95% confidence interval (CI) 0.490-0.777]}; one-sided P < 0.0001; median 13.8 (95% CI 10.1-20.7) versus 7.0 months (95% CI 5.7-9.6); overall population: HR 0.69 (95% CI 0.574-0.825); one-sided P < 0.0001; median 13.3 (95% CI 11.1-15.3) versus 8.0 months (95% CI 6.7-9.8)]. OS data were immature [PD-L1+ population: HR 0.828 (95% CI 0.596-1.151); one-sided P = 0.1301; overall population: HR 0.796 (95% CI 0.616-1.027); one-sided P = 0.0392].Conclusion Among patients with previously untreated aRCC, treatment with avelumab plus axitinib continued to result in a statistically significant improvement in PFS versus sunitinib; OS data were still immature.Clinical trial number NCT02684006..
Owen, C.N.
Shoushtari, A.N.
Chauhan, D.
Palmieri, D.J.
Lee, B.
Rohaan, M.W.
Mangana, J.
Atkinson, V.
Zaman, F.
Young, A.
Hoeller, C.
Hersey, P.
Dummer, R.
Khattak, M.A.
Millward, M.
Patel, S.P.
Haydon, A.
Johnson, D.B.
Lo, S.
Blank, C.U.
Sandhu, S.
Carlino, M.S.
Larkin, J.M.
Menzies, A.M.
Long, G.V.
(2020). Management of early melanoma recurrence despite adjuvant anti-PD-1 antibody therapy☆. Annals of oncology,
Vol.31
(8),
pp. 1075-1082.
Sud, A.
Torr, B.
Jones, M.E.
Broggio, J.
Scott, S.
Loveday, C.
Garrett, A.
Gronthoud, F.
Nicol, D.L.
Jhanji, S.
Boyce, S.A.
Williams, M.
Riboli, E.
Muller, D.C.
Kipps, E.
Larkin, J.
Navani, N.
Swanton, C.
Lyratzopoulos, G.
McFerran, E.
Lawler, M.
Houlston, R.
Turnbull, C.
(2020). Effect of delays in the 2-week-wait cancer referral pathway during the COVID-19 pandemic on cancer survival in the UK: a modelling study. The lancet. oncology,
Vol.21
(8),
pp. 1035-1044.
show abstract
Background During the COVID-19 lockdown, referrals via the 2-week-wait urgent pathway for suspected cancer in England, UK, are reported to have decreased by up to 84%. We aimed to examine the impact of different scenarios of lockdown-accumulated backlog in cancer referrals on cancer survival, and the impact on survival per referred patient due to delayed referral versus risk of death from nosocomial infection with severe acute respiratory syndrome coronavirus 2.Methods In this modelling study, we used age-stratified and stage-stratified 10-year cancer survival estimates for patients in England, UK, for 20 common tumour types diagnosed in 2008-17 at age 30 years and older from Public Health England. We also used data for cancer diagnoses made via the 2-week-wait referral pathway in 2013-16 from the Cancer Waiting Times system from NHS Digital. We applied per-day hazard ratios (HRs) for cancer progression that we generated from observational studies of delay to treatment. We quantified the annual numbers of cancers at stage I-III diagnosed via the 2-week-wait pathway using 2-week-wait age-specific and stage-specific breakdowns. From these numbers, we estimated the aggregate number of lives and life-years lost in England for per-patient delays of 1-6 months in presentation, diagnosis, or cancer treatment, or a combination of these. We assessed three scenarios of a 3-month period of lockdown during which 25%, 50%, and 75% of the normal monthly volumes of symptomatic patients delayed their presentation until after lockdown. Using referral-to-diagnosis conversion rates and COVID-19 case-fatality rates, we also estimated the survival increment per patient referred.Findings Across England in 2013-16, an average of 6281 patients with stage I-III cancer were diagnosed via the 2-week-wait pathway per month, of whom 1691 (27%) would be predicted to die within 10 years from their disease. Delays in presentation via the 2-week-wait pathway over a 3-month lockdown period (with an average presentational delay of 2 months per patient) would result in 181 additional lives and 3316 life-years lost as a result of a backlog of referrals of 25%, 361 additional lives and 6632 life-years lost for a 50% backlog of referrals, and 542 additional lives and 9948 life-years lost for a 75% backlog in referrals. Compared with all diagnostics for the backlog being done in month 1 after lockdown, additional capacity across months 1-3 would result in 90 additional lives and 1662 live-years lost due to diagnostic delays for the 25% backlog scenario, 183 additional lives and 3362 life-years lost under the 50% backlog scenario, and 276 additional lives and 5075 life-years lost under the 75% backlog scenario. However, a delay in additional diagnostic capacity with provision spread across months 3-8 after lockdown would result in 401 additional lives and 7332 life-years lost due to diagnostic delays under the 25% backlog scenario, 811 additional lives and 14 873 life-years lost under the 50% backlog scenario, and 1231 additional lives and 22 635 life-years lost under the 75% backlog scenario. A 2-month delay in 2-week-wait investigatory referrals results in an estimated loss of between 0·0 and 0·7 life-years per referred patient, depending on age and tumour type.Interpretation Prompt provision of additional capacity to address the backlog of diagnostics will minimise deaths as a result of diagnostic delays that could add to those predicted due to expected presentational delays. Prioritisation of patient groups for whom delay would result in most life-years lost warrants consideration as an option for mitigating the aggregate burden of mortality in patients with cancer.Funding None..
Sud, A.
Jones, M.E.
Broggio, J.
Loveday, C.
Torr, B.
Garrett, A.
Nicol, D.L.
Jhanji, S.
Boyce, S.A.
Gronthoud, F.
Ward, P.
Handy, J.M.
Yousaf, N.
Larkin, J.
Suh, Y.-.
Scott, S.
Pharoah, P.D.
Swanton, C.
Abbosh, C.
Williams, M.
Lyratzopoulos, G.
Houlston, R.
Turnbull, C.
(2020). Collateral damage: the impact on outcomes from cancer surgery of the COVID-19 pandemic. Annals of oncology : official journal of the european society for medical oncology,
Vol.31
(8),
pp. 1065-1074.
show abstract
Background Cancer diagnostics and surgery have been disrupted by the response of health care services to the coronavirus disease 2019 (COVID-19) pandemic. Progression of cancers during delay will impact on patients' long-term survival.Patients and methods We generated per-day hazard ratios of cancer progression from observational studies and applied these to age-specific, stage-specific cancer survival for England 2013-2017. We modelled per-patient delay of 3 and 6 months and periods of disruption of 1 and 2 years. Using health care resource costing, we contextualise attributable lives saved and life-years gained (LYGs) from cancer surgery to equivalent volumes of COVID-19 hospitalisations.Results Per year, 94 912 resections for major cancers result in 80 406 long-term survivors and 1 717 051 LYGs. Per-patient delay of 3/6 months would cause attributable death of 4755/10 760 of these individuals with loss of 92 214/208 275 life-years, respectively. For cancer surgery, average LYGs per patient are 18.1 under standard conditions and 17.1/15.9 with a delay of 3/6 months (an average loss of 0.97/2.19 LYGs per patient), respectively. Taking into account health care resource units (HCRUs), surgery results on average per patient in 2.25 resource-adjusted life-years gained (RALYGs) under standard conditions and 2.12/1.97 RALYGs following delay of 3/6 months. For 94 912 hospital COVID-19 admissions, there are 482 022 LYGs requiring 1 052 949 HCRUs. Hospitalisation of community-acquired COVID-19 patients yields on average per patient 5.08 LYG and 0.46 RALYGs.Conclusions Modest delays in surgery for cancer incur significant impact on survival. Delay of 3/6 months in surgery for incident cancers would mitigate 19%/43% of LYGs, respectively, by hospitalisation of an equivalent volume of admissions for community-acquired COVID-19. This rises to 26%/59%, respectively, when considering RALYGs. To avoid a downstream public health crisis of avoidable cancer deaths, cancer diagnostic and surgical pathways must be maintained at normal throughput, with rapid attention to any backlog already accrued..
Hall, P.E.
Shepherd, S.T.
Brown, J.
Larkin, J.
Jones, R.
Ralph, C.
Hawkins, R.
Chowdhury, S.
Boleti, E.
Bahl, A.
Fife, K.
Webb, A.
Crabb, S.J.
Geldart, T.
Hill, R.
Dunlop, J.
McLaren, D.
Ackerman, C.
Wimalasingham, A.
Beltran, L.
Nathan, P.
Powles, T.
(2020). Radiological Response Heterogeneity Is of Prognostic Significance in Metastatic Renal Cell Carcinoma Treated with Vascular Endothelial Growth Factor-targeted Therapy. European urology focus,
Vol.6
(5),
pp. 999-1005.
Khushalani, N.I.
Diab, A.
Ascierto, P.A.
Larkin, J.
Sandhu, S.
Sznol, M.
Koon, H.B.
Jarkowski, A.
Zhou, M.
Statkevich, P.
Geese, W.J.
Long, G.V.
(2020). Bempegaldesleukin plus nivolumab in untreated, unresectable or metastatic melanoma: Phase III PIVOT IO 001 study design. Future oncology,
Vol.16
(28),
pp. 2165-2175.
show abstract
Nivolumab, a PD-1 inhibitor, has demonstrated prolonged survival benefit in patients with advanced melanoma. Bempegaldesleukin (BEMPEG; NKTR-214), a first-in-class CD122-preferential IL-2 pathway agonist, provides sustained signaling through the IL-2βγ receptor, which activates effector T and natural killer cells. In the Phase I/II PIVOT-02 trial, the combination of bempegaldesleukin plus nivolumab was well-tolerated and demonstrated clinical activity as first-line therapy in metastatic melanoma. Here, we describe the design of and rationale for the Phase III, global, randomized, open-label PIVOT IO 001 trial comparing bempegaldesleukin plus nivolumab with nivolumab alone in patients with previously untreated, unresectable or metastatic melanoma. Primary end points include objective response rate, progression-free survival and overall survival. Key secondary end points include further investigation of safety/tolerability, previously assessed in the PIVOT-02 trial. Clinical Trial Registration: NCT03635983 ( ClinicalTrials.gov ) .
Comito, F.
Leslie, I.
Boos, L.
Furness, A.
Pickering, L.
Turajlic, S.
Larkin, J.
(2020). Oligoprogression After Checkpoint Inhibition in Metastatic Melanoma Treated With Locoregional Therapy: A Single-center Retrospective Analysis. Journal of immunotherapy,
Vol.43
(8),
pp. 250-255.
Motzer, R.J.
Robbins, P.B.
Powles, T.
Albiges, L.
Haanen, J.B.
Larkin, J.
Mu, X.J.
Ching, K.A.
Uemura, M.
Pal, S.K.
Alekseev, B.
Gravis, G.
Campbell, M.T.
Penkov, K.
Lee, J.L.
Hariharan, S.
Wang, X.
Zhang, W.
Wang, J.
Chudnovsky, A.
di Pietro, A.
Donahue, A.C.
Choueiri, T.K.
(2020). Avelumab plus axitinib versus sunitinib in advanced renal cell carcinoma: biomarker analysis of the phase 3 JAVELIN Renal 101 trial. Nature medicine,
Vol.26
(11),
pp. 1733-1741.
Ascierto, P.A.
Del Vecchio, M.
Mandalá, M.
Gogas, H.
Arance, A.M.
Dalle, S.
Cowey, C.L.
Schenker, M.
Grob, J.-.
Chiarion-Sileni, V.
Márquez-Rodas, I.
Butler, M.O.
Maio, M.
Middleton, M.R.
de la Cruz-Merino, L.
Arenberger, P.
Atkinson, V.
Hill, A.
Fecher, L.A.
Millward, M.
Khushalani, N.I.
Queirolo, P.
Lobo, M.
de Pril, V.
Loffredo, J.
Larkin, J.
Weber, J.
(2020). Adjuvant nivolumab versus ipilimumab in resected stage IIIB–C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial. The lancet oncology,
Vol.21
(11),
pp. 1465-1477.
de Boer, R.A.
Hulot, J.-.
Tocchetti, C.G.
Aboumsallem, J.P.
Ameri, P.
Anker, S.D.
Bauersachs, J.
Bertero, E.
Coats, A.J.
Čelutkienė, J.
Chioncel, O.
Dodion, P.
Eschenhagen, T.
Farmakis, D.
Bayes-Genis, A.
Jäger, D.
Jankowska, E.A.
Kitsis, R.N.
Konety, S.H.
Larkin, J.
Lehmann, L.
Lenihan, D.J.
Maack, C.
Moslehi, J.J.
Müller, O.J.
Nowak-Sliwinska, P.
Piepoli, M.F.
Ponikowski, P.
Pudil, R.
Rainer, P.P.
Ruschitzka, F.
Sawyer, D.
Seferovic, P.M.
Suter, T.
Thum, T.
van der Meer, P.
Van Laake, L.W.
von Haehling, S.
Heymans, S.
Lyon, A.R.
Backs, J.
(2020). Common mechanistic pathways in cancer and heart failure A scientific roadmap on behalf of the Translational Research Committee of the Heart Failure Association (HFA) of the European Society of Cardiology (ESC). ,
Vol.22
(12),
pp. 2272-2289.
show abstract
The co-occurrence of cancer and heart failure (HF) represents a significant clinical drawback as each disease interferes with the treatment of the other. In addition to shared risk factors, a growing body of experimental and clinical evidence reveals numerous commonalities in the biology underlying both pathologies. Inflammation emerges as a common hallmark for both diseases as it contributes to the initiation and progression of both HF and cancer. Under stress, malignant and cardiac cells change their metabolic preferences to survive, which makes these metabolic derangements a great basis to develop intersection strategies and therapies to combat both diseases. Furthermore, genetic predisposition and clonal haematopoiesis are common drivers for both conditions and they hold great clinical relevance in the context of personalized medicine. Additionally, altered angiogenesis is a common hallmark for failing hearts and tumours and represents a promising substrate to target in both diseases. Cardiac cells and malignant cells interact with their surrounding environment called stroma. This interaction mediates the progression of the two pathologies and understanding the structure and function of each stromal component may pave the way for innovative therapeutic strategies and improved outcomes in patients. The interdisciplinary collaboration between cardiologists and oncologists is essential to establish unified guidelines. To this aim, pre-clinical models that mimic the human situation, where both pathologies coexist, are needed to understand all the aspects of the bidirectional relationship between cancer and HF. Finally, adequately powered clinical studies, including patients from all ages, and men and women, with proper adjudication of both cancer and cardiovascular endpoints, are essential to accurately study these two pathologies at the same time..
Motzer, R.J.
Escudier, B.
George, S.
Hammers, H.J.
Srinivas, S.
Tykodi, S.S.
Sosman, J.A.
Plimack, E.R.
Procopio, G.
McDermott, D.F.
Castellano, D.
Choueiri, T.K.
Donskov, F.
Gurney, H.
Oudard, S.
Richardet, M.
Peltola, K.
Alva, A.S.
Carducci, M.
Wagstaff, J.
Chevreau, C.
Fukasawa, S.
Tomita, Y.
Gauler, T.C.
Kollmannsberger, C.K.
Schutz, F.A.
Larkin, J.
Cella, D.
McHenry, M.B.
Saggi, S.S.
Tannir, N.M.
(2020). Nivolumab versus everolimus in patients with advanced renal cell carcinoma: Updated results with long‐term follow‐up of the randomized, open‐label, phase 3 CheckMate 025 trial. Cancer,
Vol.126
(18),
pp. 4156-4167.
Dummer, R.
Hauschild, A.
Santinami, M.
Atkinson, V.
Mandalà, M.
Kirkwood, J.M.
Chiarion Sileni, V.
Larkin, J.
Nyakas, M.
Dutriaux, C.
Haydon, A.
Robert, C.
Mortier, L.
Schachter, J.
Lesimple, T.
Plummer, R.
Dasgupta, K.
Gasal, E.
Tan, M.
Long, G.V.
Schadendorf, D.
(2020). Five-Year Analysis of Adjuvant Dabrafenib plus Trametinib in Stage III Melanoma. New england journal of medicine,
Vol.383
(12),
pp. 1139-1148.
Eggermont, A.M.
Blank, C.U.
Mandala, M.
Long, G.V.
Atkinson, V.G.
Dalle, S.
Haydon, A.M.
Meshcheryakov, A.
Khattak, A.
Carlino, M.S.
Sandhu, S.
Larkin, J.
Puig, S.
Ascierto, P.A.
Rutkowski, P.
Schadendorf, D.
Koornstra, R.
Hernandez-Aya, L.
Di Giacomo, A.M.
van den Eertwegh, A.J.
Grob, J.-.
Gutzmer, R.
Jamal, R.
Lorigan, P.C.
van Akkooi, A.C.
Krepler, C.
Ibrahim, N.
Marreaud, S.
Kicinski, M.
Suciu, S.
Robert, C.
(2020). Longer Follow-Up Confirms Recurrence-Free Survival Benefit of Adjuvant Pembrolizumab in High-Risk Stage III Melanoma: Updated Results From the EORTC 1325-MG/KEYNOTE-054 Trial. J clin oncol,
Vol.38
(33),
pp. 3925-3936.
show abstract
PURPOSE: We conducted the phase III double-blind European Organisation for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial to evaluate pembrolizumab versus placebo in patients with resected high-risk stage III melanoma. On the basis of 351 recurrence-free survival (RFS) events at a 1.25-year median follow-up, pembrolizumab prolonged RFS (hazard ratio [HR], 0.57; P < .0001) compared with placebo. This led to the approval of pembrolizumab adjuvant treatment by the European Medicines Agency and US Food and Drug Administration. Here, we report an updated RFS analysis at the 3.05-year median follow-up. PATIENTS AND METHODS: A total of 1,019 patients with complete lymph node dissection of American Joint Committee on Cancer Staging Manual (seventh edition; AJCC-7), stage IIIA (at least one lymph node metastasis > 1 mm), IIIB, or IIIC (without in-transit metastasis) cutaneous melanoma were randomly assigned to receive pembrolizumab at a flat dose of 200 mg (n = 514) or placebo (n = 505) every 3 weeks for 1 year or until disease recurrence or unacceptable toxicity. The two coprimary end points were RFS in the overall population and in those with programmed death-ligand 1 (PD-L1)-positive tumors. RESULTS: Pembrolizumab (190 RFS events) compared with placebo (283 RFS events) resulted in prolonged RFS in the overall population (3-year RFS rate, 63.7% v 44.1% for pembrolizumab v placebo, respectively; HR, 0.56; 95% CI, 0.47 to 0.68) and in the PD-L1-positive tumor subgroup (HR, 0.57; 99% CI, 0.43 to 0.74). The impact of pembrolizumab on RFS was similar in subgroups, in particular according to AJCC-7 and AJCC-8 staging, and BRAF mutation status (HR, 0.51 [99% CI, 0.36 to 0.73] v 0.66 [99% CI, 0.46 to 0.95] for V600E/K v wild type). CONCLUSION: In resected high-risk stage III melanoma, pembrolizumab adjuvant therapy provided a sustained and clinically meaningful improvement in RFS at 3-year median follow-up. This improvement was consistent across subgroups..
Siddiqui, M.S.
Lai, Z.M.
Spain, L.
Greener, V.
Turajlic, S.
Larkin, J.
Morganstein, D.L.
(2020). Predicting development of ipilimumab-induced hypophysitis: utility of T4 and TSH index but not TSH. ,
Vol.44
(1),
pp. 195-203.
show abstract
PURPOSE: Ipilimumab, a monoclonal antibody inhibiting CLTA-4, is an established treatment in metastatic melanoma, either alone or in combination with nivolumab, and results in immune mediated adverse events, including endocrinopathy. Hypophysitis is one of the most common endocrine abnormalities. An early recognition of hypophysitis may prevent life threatening consequences of hypopituitarism; therefore, biomarkers to predict which patients will develop hypophysitis would have clinical utility. Recent studies suggested that a decline in TSH may serve as an early marker of IH. This study was aimed at assessing the utility of thyroid function tests in predicting development of hypophysitis. METHODS: A retrospective cohort study was performed for all patients (n = 308) treated with ipilimumab either as a monotherapy or in combination with nivolumab for advanced melanoma at the Royal Marsden Hospital from 2010 to 2016. Thyroid function tests, other pituitary function tests and Pituitary MRIs were used to identify those with hypophysitis. RESULTS AND CONCLUSIONS: Ipilimumab-induced hypophysitis (IH) was diagnosed in 25 patients (8.15%). A decline in TSH was observed in hypophysitis cohort during the first three cycles but it did not reach statistical significance (P = 0.053). A significant fall in FT4 (P < 0.001), TSH index (P < 0.001) and standardised TSH index (P < 0.001) prior to cycles 3 and 4 in hypophysitis cohort was observed. TSH is not useful in predicting development of IH. FT4, TSH index and standardised TSH index may be valuable but a high index of clinical suspicion remains paramount in early detection of hypophysitis..
Litchfield, K.
Reading, J.L.
Lim, E.L.
Xu, H.
Liu, P.
Al-Bakir, M.
Wong, Y.N.
Rowan, A.
Funt, S.A.
Merghoub, T.
Perkins, D.
Lauss, M.
Svane, I.M.
Jönsson, G.
Herrero, J.
Larkin, J.
Quezada, S.A.
Hellmann, M.D.
Turajlic, S.
Swanton, C.
(2020). Escape from nonsense-mediated decay associates with anti-tumor immunogenicity. ,
Vol.11
(1),
p. 3800.
show abstract
Frameshift insertion/deletions (fs-indels) are an infrequent but highly immunogenic mutation subtype. Although fs-indels are degraded through the nonsense-mediated decay (NMD) pathway, we hypothesise that some fs-indels escape degradation and elicit anti-tumor immune responses. Using allele-specific expression analysis, expressed fs-indels are enriched in genomic positions predicted to escape NMD, and associated with higher protein expression, consistent with degradation escape (NMD-escape). Across four independent melanoma cohorts, NMD-escape mutations are significantly associated with clinical-benefit to checkpoint inhibitor (CPI) therapy (Pmeta = 0.0039). NMD-escape mutations are additionally found to associate with clinical-benefit in the low-TMB setting. Furthermore, in an adoptive cell therapy treated melanoma cohort, NMD-escape mutation count is the most significant biomarker associated with clinical-benefit. Analysis of functional T cell reactivity screens from personalized vaccine studies shows direct evidence of fs-indel derived neoantigens eliciting immune response, particularly those with highly elongated neo open reading frames. NMD-escape fs-indels represent an attractive target for biomarker optimisation and immunotherapy design..
Larkin, J.
Brown, M.P.
Arance, A.M.
Hauschild, A.
Queirolo, P.
Vecchio, M.D.
Ascierto, P.A.
Krajsová, I.
Schachter, J.
Neyns, B.
Garbe, C.
Sileni, V.C.
Mandalà, M.
Gogas, H.
Espinosa, E.
Hospers, G.
Lorigan, P.
Nyakas, M.
Guminski, A.
Liszkay, G.
Rutkowski, P.
Miller, W.
Donica, M.
Makrutzki, M.
Blank, C.
(2019). An open-label, multicentre safety study of vemurafenib in patients with BRAFV600-mutant metastatic melanoma: final analysis and a validated prognostic scoring system. European journal of cancer,
Vol.107,
pp. 175-185.
Hayes, A.J.
Moskovic, E.
O'Meara, K.
Smith, H.G.
Pope, R.J.
Larkin, J.
Thomas, J.M.
(2019). Prospective cohort study of ultrasound surveillance of regional lymph nodes in patients with intermediate-risk cutaneous melanoma. ,
Vol.106
(6),
pp. 729-734.
show abstract
BACKGROUND: For patients with intermediate-thickness melanoma, surveillance of regional lymph node basins by clinical examination alone has been reported to result in a larger number of lymph nodes involved by melanoma than if patients had initial sentinel node biopsy and completion dissection. This may result in worse regional control. A prospective study of both regular clinical examination and ultrasound surveillance was conducted to assess the effectiveness of these modalities. METHODS: Between 2010 and 2014, patients with melanoma of thickness 1·2-3·5 mm who had under-gone wide local excision but not sentinel node biopsy were recruited to a prospective observational study of regular clinical and ultrasound nodal surveillance. The primary endpoint was nodal burden within a dissected regional lymph node basin. Secondary endpoints included locoregional or distant relapse, progression-free and overall survival. RESULTS: Ninety patients were included in the study. After a median follow-up of 52 months, ten patients had developed nodal relapse as first recurrence, four had locoregional disease outside of an anatomical nodal basin as the first site of relapse and six had relapse with distant disease. None of the patients who developed relapse within a nodal basin presented with unresectable nodal disease. The median number of involved lymph nodes in patients undergoing lymphadenectomy for nodal relapse was 1 (range 1-2; mean 1·2). CONCLUSION: This study suggests that ultrasound surveillance of regional lymph node basins is safe for patients with melanoma who undergo a policy of nodal surveillance..
Yan, Y.
Wongchenko, M.J.
Robert, C.
Larkin, J.
Ascierto, P.A.
Dréno, B.
Maio, M.
Garbe, C.
Chapman, P.B.
Sosman, J.A.
Shi, Z.
Koeppen, H.
Hsu, J.J.
Chang, I.
Caro, I.
Rooney, I.
McArthur, G.A.
Ribas, A.
(2019). Genomic Features of Exceptional Response in Vemurafenib ± Cobimetinib–treated Patients with BRAFV600-mutated Metastatic Melanoma. Clinical cancer research,
Vol.25
(11),
pp. 3239-3246.
show abstract
Abstract
Purpose: Previous investigations identified transcriptional signatures associated with innate resistance to anti–programmed cell death protein 1 therapy in melanoma. This analysis aimed to increase understanding of the role of baseline genetic features in the variability of response to BRAF and MEK inhibitor therapy for BRAFV600-mutated metastatic melanoma.
Patients and Methods: This exploratory analysis compared genomic features, using whole-exome and RNA sequencing, of baseline tumors from patients who had complete response versus rapid progression (disease progression at first postbaseline assessment) on treatment with cobimetinib combined with vemurafenib or vemurafenib alone. Associations of gene expression with progression-free survival or overall survival were assessed by Cox proportional hazards modeling.
Results: Whole-exome sequencing showed that MITF and TP53 alterations were more frequent in tumors from patients with rapid progression, while NF1 alterations were more frequent in tumors from patients with complete response. However, the low frequency of alterations in any one gene precluded their characterization as drivers of response/resistance. Analysis of RNA profiles showed that expression of immune response–related genes was enriched in tumors from patients with complete response, while expression of keratinization-related genes was enriched in tumors from patients who experienced rapid progression.
Conclusions: These findings suggest that enriched immune infiltration might be a shared feature favoring response to both targeted and immune therapies, while features of innate resistance to targeted and immune therapies were distinct..
Michaelson, M.D.
Gupta, S.
Agarwal, N.
Szmulewitz, R.
Powles, T.
Pili, R.
Bruce, J.Y.
Vaishampayan, U.
Larkin, J.
Rosbrook, B.
Wang, E.
Murphy, D.
Wang, P.
Lechuga, M.J.
Valota, O.
Shepard, D.R.
(2019). A Phase Ib Study of Axitinib in Combination with Crizotinib in Patients with Metastatic Renal Cell Cancer or Other Advanced Solid Tumors. The oncologist,
Vol.24
(9),
pp. 1151-e817.
show abstract
Abstract
Lessons Learned
The combination of axitinib and crizotinib has a manageable safety and tolerability profile, consistent with the profiles of the individual agents when administered as monotherapy. The antitumor activity reported here for the combination axitinib/crizotinib does not support further study of this combination treatment in metastatic renal cell carcinoma given the current treatment landscape.
Background
Vascular endothelial growth factor (VEGF) inhibitors have been successfully used to treat metastatic renal cell carcinoma (mRCC); however, resistance eventually develops in most cases. Tyrosine protein kinase Met (MET) expression increases following VEGF inhibition, and inhibition of both has shown additive effects in controlling tumor growth and metastasis. We therefore conducted a study of axitinib plus crizotinib in advanced solid tumors and mRCC.
Methods
This phase Ib study included a dose-escalation phase (starting doses: axitinib 3 mg plus crizotinib 200 mg) to estimate maximum tolerated dose (MTD) in patients with solid tumors and a dose-expansion phase to examine preliminary efficacy in treatment-naïve patients with mRCC. Safety, pharmacokinetics, and biomarkers were also assessed.
Results
No patients in the dose-escalation phase (n = 22) experienced dose-limiting toxicity; MTD was estimated to be axitinib 5 mg plus crizotinib 250 mg. The most common grade ≥3 adverse events were hypertension (18.2%) and fatigue (9.1%). In the dose-expansion phase, overall response rate was 30% (95% confidence interval [CI], 11.9–54.3), and progression-free survival was 5.6 months (95% CI, 3.5–not reached).
Conclusion
The combination of axitinib plus crizotinib, at estimated MTD, had a manageable safety profile and showed evidence of modest antitumor activity in mRCC.
.
Lewis, K.D.
Larkin, J.
Ribas, A.
Flaherty, K.T.
McArthur, G.A.
Ascierto, P.A.
Dréno, B.
Yan, Y.
Wongchenko, M.
McKenna, E.
Zhu, Q.
Mun, Y.
Hauschild, A.
(2019). Impact of depth of response on survival in patients treated with cobimetinib ± vemurafenib: pooled analysis of BRIM-2, BRIM-3, BRIM-7 and coBRIM. ,
Vol.121
(7),
pp. 522-528.
show abstract
BACKGROUND: This pooled analysis investigated the prognostic value of depth of response in two cohorts of patients with BRAFV600-mutated metastatic melanoma treated with vemurafenib or cobimetinib plus vemurafenib. METHODS: The data were pooled from BRIM-2, BRIM-3, BRIM-7 and coBRIM. Association of depth of response with survival was estimated by Cox proportional hazards regression, adjusted for clinically relevant covariates. Depth of response was analysed in previously identified prognostic subgroups based on disease characteristics and gene signatures. RESULTS: Greater tumour reduction and longer time to maximal response were significantly associated with longer progression-free survival (PFS) and overall survival (OS) when evaluated as continuous variables. Patients with the deepest responses had long-lasting survival outcomes (median PFS: 14 months; OS: 32 months with vemurafenib; not estimable with cobimetinib plus vemurafenib). Cobimetinib plus vemurafenib improved depth of response versus vemurafenib monotherapy regardless of other prognostic factors, including gene signatures. CONCLUSIONS: Greater depth of response was associated with improved survival, supporting its utility as a measure of treatment efficacy in melanoma and further evaluation of its incorporation into existing prognostic models. Cobimetinib plus vemurafenib improved outcomes across quartiles of response regardless of prognostic factors or gene signatures and provided durable survival benefits in patients with deep responses..
Spain, L.
Tippu, Z.
Larkin, J.M.
Carr, A.
Turajlic, S.
(2019). How we treat neurological toxicity from immune checkpoint inhibitors. ,
Vol.4
(Suppl 4),
p. e000540.
show abstract
Neurological adverse events from immune checkpoint inhibition are increasingly recognised, especially with combination anti-cytotoxic T-lymphocyte antigen 4 (CTLA4) and anti-programmed death receptor 1 (anti-PD-1) therapies. Their presenting symptoms and signs are often subacute and highly variable, reflecting the numerous components of the nervous system. Given the risk of substantial morbidity and mortality, it is important to inform patients of symptoms that may be of concern, and to assess any suspected toxicity promptly. As with other immune-related adverse events, the cornerstone of management is administration of corticosteroids. Specialist neurology input is vital in this group of patients to guide appropriate investigations and tailor treatment strategies..
Johansson, M.
Carreras-Torres, R.
Scelo, G.
Purdue, M.P.
Mariosa, D.
Muller, D.C.
Timpson, N.J.
Haycock, P.C.
Brown, K.M.
Wang, Z.
Ye, Y.
Hofmann, J.N.
Foll, M.
Gaborieau, V.
Machiela, M.J.
Colli, L.M.
Li, P.
Garnier, J.-.
Blanche, H.
Boland, A.
Burdette, L.
Prokhortchouk, E.
Skryabin, K.G.
Yeager, M.
Radojevic-Skodric, S.
Ognjanovic, S.
Foretova, L.
Holcatova, I.
Janout, V.
Mates, D.
Mukeriya, A.
Rascu, S.
Zaridze, D.
Bencko, V.
Cybulski, C.
Fabianova, E.
Jinga, V.
Lissowska, J.
Lubinski, J.
Navratilova, M.
Rudnai, P.
Benhamou, S.
Cancel-Tassin, G.
Cussenot, O.
Weiderpass, E.
Ljungberg, B.
Tumkur Sitaram, R.
Häggström, C.
Bruinsma, F.
Jordan, S.J.
Severi, G.
Winship, I.
Hveem, K.
Vatten, L.J.
Fletcher, T.
Larsson, S.C.
Wolk, A.
Banks, R.E.
Selby, P.J.
Easton, D.F.
Andreotti, G.
Beane Freeman, L.E.
Koutros, S.
Männistö, S.
Weinstein, S.
Clark, P.E.
Edwards, T.L.
Lipworth, L.
Gapstur, S.M.
Stevens, V.L.
Carol, H.
Freedman, M.L.
Pomerantz, M.M.
Cho, E.
Wilson, K.M.
Gaziano, J.M.
Sesso, H.D.
Freedman, N.D.
Parker, A.S.
Eckel-Passow, J.E.
Huang, W.-.
Kahnoski, R.J.
Lane, B.R.
Noyes, S.L.
Petillo, D.
Teh, B.T.
Peters, U.
White, E.
Anderson, G.L.
Johnson, L.
Luo, J.
Buring, J.
Lee, I.-.
Chow, W.-.
Moore, L.E.
Eisen, T.
Henrion, M.
Larkin, J.
Barman, P.
Leibovich, B.C.
Choueiri, T.K.
Lathrop, G.M.
Deleuze, J.-.
Gunter, M.
McKay, J.D.
Wu, X.
Houlston, R.S.
Chanock, S.J.
Relton, C.
Richards, J.B.
Martin, R.M.
Davey Smith, G.
Brennan, P.
(2019). The influence of obesity-related factors in the etiology of renal cell carcinoma-A mendelian randomization study. Plos medicine,
Vol.16
(1),
pp. e1002724-?.
show abstract
Background Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation.Methods and findings Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44-1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40-1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44-1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30-2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11-1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84-1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose.Conclusions This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk..
Robert, C.
Flaherty, K.
Nathan, P.
Hersey, P.
Garbe, C.
Milhem, M.
Demidov, L.
Mohr, P.
Hassel, J.C.
Rutkowski, P.
Dummer, R.
Utikal, J.
Kiecker, F.
Larkin, J.
D'Amelio, A.
Mookerjee, B.
Schadendorf, D.
(2019). Five-year outcomes from a phase 3 METRIC study in patients with BRAF V600 E/K–mutant advanced or metastatic melanoma. European journal of cancer,
Vol.109,
pp. 61-69.
Ingles Garces, A.H.
Au, L.
Mason, R.
Thomas, J.
Larkin, J.
(2019). Building on the anti-PD1/PD-L1 backbone: combination immunotherapy for cancer. Expert opinion on investigational drugs,
Vol.28
(8),
pp. 695-708.
Schadendorf, D.
Hauschild, A.
Santinami, M.
Atkinson, V.
Mandalà, M.
Chiarion-Sileni, V.
Larkin, J.
Nyakas, M.
Dutriaux, C.
Haydon, A.
Robert, C.
Mortier, L.
Lesimple, T.
Plummer, R.
Schachter, J.
Dasgupta, K.
Manson, S.
Koruth, R.
Mookerjee, B.
Kefford, R.
Dummer, R.
Kirkwood, J.M.
Long, G.V.
(2019). Patient-reported outcomes in patients with resected, high-risk melanoma with BRAFV600E or BRAFV600K mutations treated with adjuvant dabrafenib plus trametinib (COMBI-AD): a randomised, placebo-controlled, phase 3 trial. The lancet oncology,
Vol.20
(5),
pp. 701-710.
Lewis, K.
Hauschild, A.
Larkin, J.
Ribas, A.
Flaherty, K.T.
McArthur, G.A.
Dréno, B.
McKenna, E.
Zhu, Q.
Mun, Y.
Ascierto, P.A.
(2019). Effect of concomitant dosing with acid-reducing agents and vemurafenib dose on survival in patients with BRAFV600 mutation–positive metastatic melanoma treated with vemurafenib ± cobimetinib. European journal of cancer,
Vol.116,
pp. 45-55.
Kreft, S.
Gesierich, A.
Eigentler, T.
Franklin, C.
Valpione, S.
Ugurel, S.
Utikal, J.
Haferkamp, S.
Blank, C.
Larkin, J.
Garbe, C.
Schadendorf, D.
Lorigan, P.
Schilling, B.
(2019). Efficacy of PD-1–based immunotherapy after radiologic progression on targeted therapy in stage IV melanoma. European journal of cancer,
Vol.116,
pp. 207-215.
Eggermont, A.M.
Blank, C.U.
Mandala, M.
Long, G.V.
Atkinson, V.G.
Dalle, S.
Haydon, A.
Lichinitser, M.
Khattak, A.
Carlino, M.S.
Sandhu, S.
Larkin, J.
Puig, S.
Ascierto, P.A.
Rutkowski, P.
Schadendorf, D.
Koornstra, R.
Hernandez-Aya, L.
Di Giacomo, A.M.
van den Eertwegh, A.J.
Grob, J.-.
Gutzmer, R.
Jamal, R.
Lorigan, P.C.
Lupinacci, R.
Krepler, C.
Ibrahim, N.
Kicinski, M.
Marreaud, S.
van Akkooi, A.C.
Suciu, S.
Robert, C.
(2019). Prognostic and predictive value of AJCC-8 staging in the phase III EORTC1325/KEYNOTE-054 trial of pembrolizumab vs placebo in resected high-risk stage III melanoma. European journal of cancer,
Vol.116,
pp. 148-157.
Long, G.V.
Dummer, R.
Hamid, O.
Gajewski, T.F.
Caglevic, C.
Dalle, S.
Arance, A.
Carlino, M.S.
Grob, J.-.
Kim, T.M.
Demidov, L.
Robert, C.
Larkin, J.
Anderson, J.R.
Maleski, J.
Jones, M.
Diede, S.J.
Mitchell, T.C.
(2019). Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252): a phase 3, randomised, double-blind study. The lancet oncology,
Vol.20
(8),
pp. 1083-1097.
Robert, C.
Ribas, A.
Schachter, J.
Arance, A.
Grob, J.-.
Mortier, L.
Daud, A.
Carlino, M.S.
McNeil, C.M.
Lotem, M.
Larkin, J.M.
Lorigan, P.
Neyns, B.
Blank, C.U.
Petrella, T.M.
Hamid, O.
Su, S.-.
Krepler, C.
Ibrahim, N.
Long, G.V.
(2019). Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. The lancet oncology,
Vol.20
(9),
pp. 1239-1251.
Regan, M.M.
Werner, L.
Rao, S.
Gupte-Singh, K.
Hodi, F.S.
Kirkwood, J.M.
Kluger, H.M.
Larkin, J.
Postow, M.A.
Ritchings, C.
Sznol, M.
Tarhini, A.A.
Wolchok, J.D.
Atkins, M.B.
McDermott, D.F.
(2019). Treatment-Free Survival: A Novel Outcome Measure of the Effects of Immune Checkpoint Inhibition-A Pooled Analysis of Patients With Advanced Melanoma. ,
Vol.37
(35),
pp. 3350-3358.
show abstract
PURPOSE: Outcome measures that comprehensively capture attributes of immuno-oncology agents, including prolonged treatment-free time and persistent treatment-related adverse events (TRAEs), are needed to complement conventional survival end points. METHODS: We pooled data from the CheckMate 067 and 069 clinical trials of nivolumab and ipilimumab, as monotherapies or in combination, for patients with advanced melanoma. Treatment-free survival (TFS) was defined as the area between Kaplan-Meier curves for two conventional time-to-event end points, each defined from random assignment: time to immune checkpoint inhibitor (ICI) protocol therapy cessation and time to subsequent systemic therapy initiation or death. TFS was partitioned as time with and without toxicity by a third end point, time to cessation of both ICI therapy and toxicity. Toxicity included persistent and late-onset grade 3 or higher TRAEs. The area under each Kaplan-Meier curve was estimated by the 36-month restricted mean time. RESULTS: At 36 months, many of the 1,077 patients who initiated ICI therapy were surviving free of subsequent therapy initiation (47% nivolumab plus ipilimumab, 37% nivolumab, 15% ipilimumab). The restricted mean TFS was longer for nivolumab plus ipilimumab (11.1 months) compared with nivolumab (4.6 months; difference, 6.5 months; 95% CI, 5.0 to 8.0 months) or ipilimumab (8.7 months; difference, 2.4 months; 95% CI, 0.8 to 4.1 months); restricted mean TFS represented 31% (3% with and 28% without toxicity), 13% (1% and 11%), and 24% (less than 1% and 23%) of the 36-month period, respectively, in the three treatment groups. TFS without toxicity was longer for nivolumab plus ipilimumab than nivolumab (difference, 6.0 months) or ipilimumab (difference, 1.7 months). CONCLUSION: The analysis of TFS between ICI cessation and subsequent therapy initiation revealed longer TFS without toxicity for patients with advanced melanoma who received nivolumab plus ipilimumab compared with nivolumab or ipilimumab. Regardless of treatment, a small proportion of the TFS involved grade 3 or higher TRAEs..
Mason, R.
Au, L.
Ingles Garces, A.
Larkin, J.
(2019). Current and emerging systemic therapies for cutaneous metastatic melanoma. Expert opinion on pharmacotherapy,
Vol.20
(9),
pp. 1135-1152.
Buckley, H.L.
Collinson, F.J.
Ainsworth, G.
Poad, H.
Flanagan, L.
Katona, E.
Howard, H.C.
Murden, G.
Banks, R.E.
Brown, J.
Velikova, G.
Waddell, T.
Fife, K.
Nathan, P.D.
Larkin, J.
Powles, T.
Brown, S.R.
Vasudev, N.S.
(2019). PRISM protocol: a randomised phase II trial of nivolumab in combination with alternatively scheduled ipilimumab in first-line treatment of patients with advanced or metastatic renal cell carcinoma. Bmc cancer,
Vol.19
(1),
pp. 1102-?.
show abstract
BACKGROUND:The combination of nivolumab, a programmed death-1 (PD-1) targeted monoclonal antibody, with the cytotoxic T-lymphocyte antigen-4 (CTLA-4) targeted antibody, ipilimumab, represents a new standard of care in the first-line setting for patients with intermediate- and poor-risk metastatic renal cell carcinoma (mRCC) based on recent phase III data. Combining ipilimumab with nivolumab increases rates of grade 3 and 4 toxicity compared with nivolumab alone, and the optimal scheduling of these agents when used together remains unknown. The aim of the PRISM study is to assess whether less frequent dosing of ipilimumab (12-weekly versus 3-weekly), in combination with nivolumab, is associated with a favourable toxicity profile without adversely impacting efficacy. METHODS:The PRISM trial is a UK-based, open label, multi-centre, phase II, randomised controlled trial. The trial population consists of patients with untreated locally advanced or metastatic clear cell RCC, and aims to recruit 189 participants. Participants will be randomised on a 2:1 basis in favour of a modified schedule of 4 doses of 12-weekly ipilimumab versus a standard schedule of 4 doses of 3-weekly ipilimumab, both in combination with standard nivolumab. The proportion of participants experiencing a grade 3 or 4 adverse reaction within 12 months forms the primary endpoint of the study, but with 12-month progression free survival a key secondary endpoint. The incidence of all adverse events, discontinuation rates, overall response rate, duration of response, overall survival rates and health related quality of life will also be analysed as secondary endpoints. In addition, the potential of circulating and tissue-based biomarkers as predictors of therapy response will be explored. DISCUSSION:The combination of nivolumab with ipilimumab is active in patients with mRCC. Modifying the frequency of ipilimumab dosing may mitigate toxicity rates and positively impact quality of life without compromising efficacy, a hypothesis being explored in other tumour types such as non-small cell lung cancer. The best way to give this combination to patients with mRCC must be similarly established. TRIAL REGISTRATION:PRISM is registered with ISRCTN (reference ISRCTN95351638, 19/12/2017). TRIAL STATUS:At the time of submission, PRISM is open to recruitment and data collection is ongoing..
Larkin, J.
Chiarion-Sileni, V.
Gonzalez, R.
Grob, J.-.
Rutkowski, P.
Lao, C.D.
Cowey, C.L.
Schadendorf, D.
Wagstaff, J.
Dummer, R.
Ferrucci, P.F.
Smylie, M.
Hogg, D.
Hill, A.
Márquez-Rodas, I.
Haanen, J.
Guidoboni, M.
Maio, M.
Schöffski, P.
Carlino, M.S.
Lebbé, C.
McArthur, G.
Ascierto, P.A.
Daniels, G.A.
Long, G.V.
Bastholt, L.
Rizzo, J.I.
Balogh, A.
Moshyk, A.
Hodi, F.S.
Wolchok, J.D.
(2019). Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. New england journal of medicine,
Vol.381
(16),
pp. 1535-1546.
Motzer, R.J.
Penkov, K.
Haanen, J.
Rini, B.
Albiges, L.
Campbell, M.T.
Venugopal, B.
Kollmannsberger, C.
Negrier, S.
Uemura, M.
Lee, J.L.
Vasiliev, A.
Miller, W.H.
Gurney, H.
Schmidinger, M.
Larkin, J.
Atkins, M.B.
Bedke, J.
Alekseev, B.
Wang, J.
Mariani, M.
Robbins, P.B.
Chudnovsky, A.
Fowst, C.
Hariharan, S.
Huang, B.
di Pietro, A.
Choueiri, T.K.
(2019). Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. New england journal of medicine,
Vol.380
(12),
pp. 1103-1115.
Valpione, S.
Carlino, M.S.
Mangana, J.
Mooradian, M.J.
McArthur, G.
Schadendorf, D.
Hauschild, A.
Menzies, A.M.
Arance, A.
Ascierto, P.A.
Di Giacomo, A.
de Rosa, F.
Larkin, J.
Park, J.J.
Goldinger, S.M.
Sullivan, R.J.
Xu, W.
Livingstone, E.
Weichenthal, M.
Rai, R.
Gaba, L.
Long, G.V.
Lorigan, P.
(2018). Rechallenge with BRAF-directed treatment in metastatic melanoma: A multi-institutional retrospective study. ,
Vol.91,
pp. 116-124.
show abstract
BACKGROUND: Most metastatic melanoma patients treated with BRAF inhibitors (BRAFi) ± MEK inhibitors (MEKi) eventually progress on treatment. Along with acquired resistance due to genetic changes, epigenetic mechanisms that could be reversed after BRAFi discontinuation have been described. The purpose of this study was to analyse retrospectively outcomes for patients retreated with BRAF-directed therapy. PATIENTS AND METHODS: One hundred sixteen metastatic melanoma patients who received BRAFi-based therapy and, after a break, were rechallenged with BRAFi ± MEKi at 14 centres in Europe, US and Australia were studied, respectively. Response rate (RR), overall survival (OS) and progression-free survival (PFS) from the start of retreatment were calculated. RESULTS: The median duration of treatment was 9.4 months for first BRAFi ± MEKi treatment and 7.7 months for the subsequent treatment (immunotherapy 72%, other 17%, drug holiday 11%) after BRAFi discontinuation. Brain metastases were present in 51 (44%) patients at BRAFi retreatment. The RR to rechallenge with BRAFi ± MEKi was 43.3%: complete response (CR) 2.6%, partial response (PR) 40.7%, stable disease (SD) 24.8% and progressive disease 31.9%, 3 missing. Of 83 patients who previously discontinued BRAFi due to disease progression, 31 (37.3%) responded (30 PR and 1 CR) to retreatment. The median OS from retreatment was 9.8 months, and PFS was 5 months. Independent prognostic factors for survival at rechallenge included number of metastatic sites (hazard ratio [HR] = 1.32 for each additional organ with metastases, P < .001), lactic dehydrogenase (HR = 1.37 for each multiple of the upper normal limit, P < .001), while rechallenge with combination BRAFi + MEKi conferred a better OS versus BRAFi alone (HR = 0.5, P = .006). CONCLUSION: Rechallenge with BRAFi ± MEKi results in a clinically meaningful benefit and should be considered for selected patients..
Lim, K.H.
Spain, L.
Barker, C.
Georgiou, A.
Walls, G.
Gore, M.
Turajlic, S.
Board, R.
Larkin, J.M.
Lorigan, P.
(2018). Contemporary outcomes from the use of regular imaging to detect relapse in high-risk cutaneous melanoma. Esmo open,
Vol.3
(2),
pp. e000317-?.
show abstract
Background:Agreement on the utility of imaging follow-up in patients with high-risk melanoma is lacking. A UK consensus statement recommends a surveillance schedule of CT or positron-emission tomography-CT and MRI brain (every 6 months for 3 years, then annually in years 4 and 5) as well as clinical examination for high-risk resected Stages II and III cutaneous melanoma. Our aim was to assess patterns of relapse and whether imaging surveillance could be of clinical benefit. Patients and methods:A retrospective study of patients enrolled between July 2013 and June 2015 from three UK tertiary cancer centres followed-up according to this protocol was undertaken. We evaluated time-to-recurrence (TTR), recurrence-free survival (RFS), method of detection and characteristics of recurrence, treatment received and overall survival (OS). Results:A total of 173 patients were included. Most (79%) had treated Stages IIIB and IIIC disease. With a median follow-up of 23.3 months, 82 patients (47%) had relapsed. Median TTR was 10.1 months and median RFS was 21.2 months. The majority of recurrences (66%) were asymptomatic and detected by scheduled surveillance scan. Fifty-six (68%) patients recurred with Stage IV disease, with a median OS of 25.3 months; 26 (31.7%) patients had a locoregional recurrence, median OS not reached (P=0.016). Patients who underwent surgery at recurrence for either Stage III (27%) or IV (18%) disease did not reach their median OS. The median OS for the 33 patients (40%) who received systemic therapy was 12.9 months. Conclusion:Imaging appears to reliably detect subclinical disease and identify patients suitable for surgery, conferring favourable outcomes. The short median TTR provides rationale to intensify imaging schedule in the first year of surveillance. The poor OS of patients treated with systemic therapy probably reflects the relatively inferior treatment options during this time and requires further evaluation in the current era..
Flynn, M.
Pickering, L.
Larkin, J.
Turajlic, S.
(2018). Immune-checkpoint inhibitors in melanoma and kidney cancer: from sequencing to rational selection. Therapeutic advances in medical oncology,
Vol.10,
pp. 1758835918777427-?.
show abstract
Immune-checkpoint inhibitors (ICPIs), including antibodies against cytotoxic T-lymphocyte associated antigen 4 and programmed cell death protein 1, have been shown to induce durable complete responses in a proportion of patients in the first-line and refractory setting in advanced melanoma and renal cell carcinoma. In fact, there are several lines of both targeted agents and ICPI that are now feasible treatment options. However, survival in the metastatic setting continues to be poor and there remains a need for improved therapeutic approaches. In order to enhance patient selection for the most appropriate next line of therapy, better predictive biomarkers of responsiveness will need to be developed in tandem with technologies to identify mechanisms of ICPI resistance. Adaptive, biomarker-driven trials will drive this evolution. The combination of ICPI with specific chemotherapies, targeted therapies and other immuno-oncology (IO) drugs in order to circumvent ICPI resistance and enhance efficacy is discussed. Recent data support the role for both targeted therapies and ICPI in the adjuvant setting of melanoma and targeted therapies in the adjuvant setting for renal cell carcinoma, which may influence the consideration of treatment on subsequent relapse. Approaches to select the optimal treatment sequences for these patients will need to be refined..
Hauschild, A.
Larkin, J.
Ribas, A.
Dréno, B.
Flaherty, K.T.
Ascierto, P.A.
Lewis, K.D.
McKenna, E.
Zhu, Q.
Mun, Y.
McArthur, G.A.
(2018). Modeled Prognostic Subgroups for Survival and Treatment Outcomes in BRAF V600–Mutated Metastatic Melanoma. Jama oncology,
Vol.4
(10),
pp. 1382-1382.
Higham, C.E.
Olsson-Brown, A.
Carroll, P.
Cooksley, T.
Larkin, J.
Lorigan, P.
Morganstein, D.
Trainer, P.J.
Society for Endocrinology Clinical Committee,
(2018). SOCIETY FOR ENDOCRINOLOGY ENDOCRINE EMERGENCY GUIDANCE: Acute management of the endocrine complications of checkpoint inhibitor therapy. ,
Vol.7
(7),
pp. G1-G7.
show abstract
Immunotherapy treatment with checkpoint inhibitors (CPI) (CTLA-4 and PD-1 inhibitors) significantly improves survival in a number of cancers. Treatment can be limited by immune-mediated adverse effects including endocrinopathies such as hypophysitis, adrenalitis, thyroiditis and diabetes mellitus. If endocrinopathies (particularly hypocortisolemia) are not recognized early, they can be fatal. The diagnosis and management of endocrinopathies can be complicated by simultaneous multi-organ immune adverse effects. Here, we present Endocrine Emergency Guidance for the acute management of the endocrine complications of checkpoint inhibitor therapy, the first specialty-specific guidance with Endocrinology, Oncology and Acute Medicine input and endorsed by the Society for Endocrinology Clinical Committee. We present algorithms for management: endocrine assessment and management of patients in the first 24 hours who present life-threateningly unwell (CTCAE grade 3-4) and the appropriate management of mild-moderately unwell patients (CTCAE grade 1-2) presenting with features compatible with an endocrinopathy. Other important considerations in relation to hypohysitis and the maintenance of glucocorticoid therapy are discussed..
Larkin, J.
Minor, D.
D'Angelo, S.
Neyns, B.
Smylie, M.
Miller, W.H.
Gutzmer, R.
Linette, G.
Chmielowski, B.
Lao, C.D.
Lorigan, P.
Grossmann, K.
Hassel, J.C.
Sznol, M.
Daud, A.
Sosman, J.
Khushalani, N.
Schadendorf, D.
Hoeller, C.
Walker, D.
Kong, G.
Horak, C.
Weber, J.
(2018). Overall Survival in Patients With Advanced Melanoma Who Received Nivolumab Versus Investigator's Choice Chemotherapy in CheckMate 037: A Randomized, Controlled, Open-Label Phase III Trial. Journal of clinical oncology : official journal of the american society of clinical oncology,
Vol.36
(4),
pp. 383-390.
show abstract
Purpose Until recently, limited options existed for patients with advanced melanoma who experienced disease progression while receiving treatment with ipilimumab. Here, we report the coprimary overall survival (OS) end point of CheckMate 037, which has previously shown that nivolumab resulted in more patients achieving an objective response compared with chemotherapy regimens in ipilimumab-refractory patients with advanced melanoma. Patients and Methods Patients were stratified by programmed death-ligand 1 expression, BRAF status, and best prior cytotoxic T-lymphocyte antigen-4 therapy response, then randomly assigned 2:1 to nivolumab 3 mg/kg intravenously every 2 weeks or investigator's choice chemotherapy (ICC; dacarbazine 1,000 mg/m 2 every 3 weeks or carboplatin area under the curve 6 plus paclitaxel 175 mg/m 2 every 3 weeks). Patients were treated until they experienced progression or unacceptable toxicity, with follow-up of approximately 2 years. Results Two hundred seventy-two patients were randomly assigned to nivolumab (99% treated) and 133 to ICC (77% treated). More nivolumab-treated patients had brain metastases (20% v 14%) and increased lactate dehydrogenase levels (52% v 38%) at baseline; 41% of patients treated with ICC versus 11% of patients treated with nivolumab received anti-programmed death 1 agents after randomly assigned therapy. Median OS was 16 months for nivolumab versus 14 months for ICC (hazard ratio, 0.95; 95.54% CI, 0.73 to 1.24); median progression-free survival was 3.1 months versus 3.7 months, respectively (hazard ratio, 1.0; 95.1% CI, 0.78 to 1.436). Overall response rate (27% v 10%) and median duration of response (32 months v 13 months) were notably higher for nivolumab versus ICC. Fewer grade 3 and 4 treatment-related adverse events were observed in patients on nivolumab (14% v 34%). Conclusion Nivolumab demonstrated higher, more durable responses but no difference in survival compared with ICC. OS should be interpreted with caution as it was likely impacted by an increased dropout rate before treatment, which led to crossover therapy in the ICC group, and by an increased proportion of patients in the nivolumab group with poor prognostic factors..
Grob, J.J.
Schadendorf, D.
Lorigan, P.
Ascierto, P.
Larkin, J.
Nathan, P.
Robert, C.
Hauschild, A.
Weber, J.
Daud, A.
Hamid, O.
Dummer, R.
Hansson, J.
Hoeller, C.
Schachter, J.
Van Akkooi, A.C.
Garbe, C.
(2018). Eighth American Joint Committee on Cancer (AJCC) melanoma classification: Let us reconsider stage III. European journal of cancer (oxford, england : 1990),
Vol.91,
pp. 168-170.
Yip, K.
Melcher, A.
Harrington, K.
Illidge, T.
Nobes, J.
Webster, A.
Smith, D.
Lorigan, P.
Nathan, P.
Larkin, J.
(2018). Pembrolizumab in Combination with Radiotherapy for Metastatic Melanoma - Introducing the PERM Trial. Clinical oncology (royal college of radiologists (great britain)),
Vol.30
(4),
pp. 201-203.
Choueiri, T.K.
Larkin, J.
Oya, M.
Thistlethwaite, F.
Martignoni, M.
Nathan, P.
Powles, T.
McDermott, D.
Robbins, P.B.
Chism, D.D.
Cho, D.
Atkins, M.B.
Gordon, M.S.
Gupta, S.
Uemura, H.
Tomita, Y.
Compagnoni, A.
Fowst, C.
di Pietro, A.
Rini, B.I.
(2018). Preliminary results for avelumab plus axitinib as first-line therapy in patients with advanced clear-cell renal-cell carcinoma (JAVELIN Renal 100): an open-label, dose-finding and dose-expansion, phase 1b trial. The lancet oncology,
Vol.19
(4),
pp. 451-460.
Arce Vargas, F.
Furness, A.J.
Litchfield, K.
Joshi, K.
Rosenthal, R.
Ghorani, E.
Solomon, I.
Lesko, M.H.
Ruef, N.
Roddie, C.
Henry, J.Y.
Spain, L.
Ben Aissa, A.
Georgiou, A.
Wong, Y.N.
Smith, M.
Strauss, D.
Hayes, A.
Nicol, D.
O'Brien, T.
Mårtensson, L.
Ljungars, A.
Teige, I.
Frendéus, B.
TRACERx Melanoma,
TRACERx Renal,
TRACERx Lung consortia,
Pule, M.
Marafioti, T.
Gore, M.
Larkin, J.
Turajlic, S.
Swanton, C.
Peggs, K.S.
Quezada, S.A.
(2018). Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies. Cancer cell,
Vol.33
(4),
pp. 649-663.e4.
show abstract
With the use of a mouse model expressing human Fc-gamma receptors (FcγRs), we demonstrated that antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion in vivo, increasing the CD8+ to Treg cell ratio and promoting tumor rejection. Antibodies with improved FcγR binding profiles drove superior anti-tumor responses and survival. In patients with advanced melanoma, response to ipilimumab was associated with the CD16a-V158F high affinity polymorphism. Such activity only appeared relevant in the context of inflamed tumors, explaining the modest response rates observed in the clinical setting. Our data suggest that the activity of anti-CTLA-4 in inflamed tumors may be improved through enhancement of FcγR binding, whereas poorly infiltrated tumors will likely require combination approaches..
Wongchenko, M.J.
Ribas, A.
Dréno, B.
Ascierto, P.A.
McArthur, G.A.
Gallo, J.D.
Rooney, I.A.
Hsu, J.
Koeppen, H.
Yan, Y.
Larkin, J.
(2018). Association of programmed death ligand-1 (PD-L1) expression with treatment outcomes in patients with BRAF mutation-positive melanoma treated with vemurafenib or cobimetinib combined with vemurafenib. Pigment cell & melanoma research,
Vol.31
(4),
pp. 516-522.
show abstract
The prognostic significance of programmed death ligand-1 (PD-L1) on treatment outcomes in patients receiving BRAF with or without MEK inhibitors is not well understood. This retrospective exploratory analysis evaluated the association of tumour PD-L1 expression with progression-free survival (PFS) and overall survival (OS) among 210 patients in the coBRIM trial treated with cobimetinib plus vemurafenib or placebo plus vemurafenib. In the vemurafenib cohort, there was a trend of increased PFS and OS in those with PD-L1+ melanoma, with hazard ratios (HRs; PD-L1+ vs. PD-L1- ) of 0.70 (95% CI, 0.46-1.07) and 0.69 (95% CI, 0.42-1.13) for PFS and OS, respectively. However, in patients treated with cobimetinib plus vemurafenib, a similar trend was not observed with HRs (PD-L1+ versus PD-L1- ) of 1.04 (95% CI, 0.66-1.68) and 0.94 (95% CI, 0.57-1.57) for PFS and OS, respectively. The combination cobimetinib plus vemurafenib appears to overcome the poor prognosis associated with low PD-L1 expression..
Lyon, A.R.
Yousaf, N.
Battisti, N.M.
Moslehi, J.
Larkin, J.
(2018). Immune checkpoint inhibitors and cardiovascular toxicity. The lancet oncology,
Vol.19
(9),
pp. e447-e458.
Sun, M.
Marconi, L.
Eisen, T.
Escudier, B.
Giles, R.H.
Haas, N.B.
Harshman, L.C.
Quinn, D.I.
Larkin, J.
Pal, S.K.
Powles, T.
Ryan, C.W.
Sternberg, C.N.
Uzzo, R.
Choueiri, T.K.
Bex, A.
(2018). Adjuvant Vascular Endothelial Growth Factor–targeted Therapy in Renal Cell Carcinoma: A Systematic Review and Pooled Analysis. European urology,
Vol.74
(5),
pp. 611-620.
Smith, M.J.
Smith, H.G.
Joshi, K.
Gore, M.
Strauss, D.C.
Hayes, A.J.
Larkin, J.
(2018). The impact of effective systemic therapies on surgery for stage IV melanoma. European journal of cancer,
Vol.103,
pp. 24-31.
Hodi, F.S.
Chiarion-Sileni, V.
Gonzalez, R.
Grob, J.-.
Rutkowski, P.
Cowey, C.L.
Lao, C.D.
Schadendorf, D.
Wagstaff, J.
Dummer, R.
Ferrucci, P.F.
Smylie, M.
Hill, A.
Hogg, D.
Marquez-Rodas, I.
Jiang, J.
Rizzo, J.
Larkin, J.
Wolchok, J.D.
(2018). Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. The lancet oncology,
Vol.19
(11),
pp. 1480-1492.
Wongchenko, M.J.
Ribas, A.
Ascierto, P.A.
Dréno, B.
Maria di Giacomo, A.
Garbe, C.
Chang, I.
Hsu, J.
Rooney, I.
Lu, W.
Koeppen, H.
Larkin, J.
Yan, Y.
McArthur, G.A.
(2018). Effects of Molecular Heterogeneity on Survival of Patients With BRAFV600-Mutated Melanoma Treated With Vemurafenib With or Without Cobimetinib in the coBRIM Study. Jco precision oncology,
(2),
pp. 1-18.
show abstract
Purpose The treatment of advanced BRAFV600-mutated melanomas with BRAF inhibitors (BRAFi) has improved survival, but the efficacy of BRAFi varies among individuals and the development of acquired resistance to BRAFi through reactivation of mitogen-activated protein kinase (MAPK) signaling is common. We performed an exploratory, retrospective analysis to investigate the effects of BRAFV600 allelic balance, coexisting oncogene mutations, cell proliferation signaling levels, and loss of PTEN expression on progression-free survival (PFS) in patients in the phase III coBRIM study, which compared the combination of the MEK inhibitor cobimetinib with the BRAFi vemurafenib versus vemurafenib as monotherapy. Methods Baseline tumor samples from the intention-to-treat population were analyzed by targeted deep sequencing at a median coverage of 3,600× and by immunohistochemistry for cell proliferation markers, BRAFV600E, and PTEN. The association of these biomarkers with PFS was assessed by Cox proportional hazards modeling. Gene expression in relation to loss of PTEN was profiled by RNA sequencing in 205 patient samples and 42 BRAFV600-mutated melanoma cell lines. Results Neither BRAFV600 allelic balance nor coexisting mutations in the RAS/RAF/RTK pathway affected PFS in either treatment group. Increased baseline MAPK signaling and cell proliferation did not affect PFS in patients treated with cobimetinib combined with vemurafenib. PTEN loss was associated with reduced PFS in patients treated with vemurafenib alone but not in patients treated with cobimetinib combined with vemurafenib. Conclusion Deeper inhibition of the MAPK pathway through targeting of both MEK and BRAF may override the effects of tumor heterogeneity and improve PFS in all patients with advanced BRAFV600 melanoma. .
Lu, W.
Burton, L.
Larkin, J.
Chapman, P.B.
Ascierto, P.A.
Ribas, A.
Robert, C.
Sosman, J.A.
McArthur, G.A.
Chang, I.
Caro, I.
Penuel, E.
Yan, Y.
Wongchenko, M.J.
(2018). Elevated Levels of BRAFV600 Mutant Circulating Tumor DNA and Circulating Hepatocyte Growth Factor Are Associated With Poor Prognosis in Patients With Metastatic Melanoma. Jco precision oncology,
(2),
pp. 1-17.
show abstract
Purpose We performed a retrospective exploratory analysis to evaluate the prognostic and predictive effect of two circulating biomarkers, BRAFV600 mutant circulating tumor DNA (ctDNA) and circulating hepatocyte growth factor (cHGF), in metastatic melanoma. Materials and Methods This study evaluated patients from BRIM-3, a phase III trial comparing vemurafenib and dacarbazine in 675 patients with BRAFV600 mutated advanced melanoma. ctDNA was measured using droplet digital polymerase chain reaction, and cHGF was measured by enzyme-linked immunosorbent assay. Overall survival (OS) was estimated using the Kaplan-Meier method, and hazard ratios (HRs) were estimated using Cox proportional hazards modeling. Partitioning analysis was used to group patients into risk categories. Results Patients with elevated levels of baseline BRAFV600 ctDNA had significantly shorter median OS than those with undetectable levels of ctDNA (vemurafenib arm, 9.9 v 21.4 months, respectively, and dacarbazine arm: 6.1 v 21.0 months, respectively). Median OS was also shorter in patients with high levels of cHGF compared with those with low cHGF (vemurafenib arm, 11.9 v 17.3 months, respectively, and dacarbazine arm, 6.1 v 14.4 months, respectively). In a multivariable proportional hazards model with adjustment for lactate dehydrogenase, Eastern Cooperative Oncology Group status, disease stage, and treatment, ctDNA and cHGF were both independent prognostic factors for OS, (HR, 1.75; 95% CI, 1.35 to 2.28 for high v undetectable ctDNA; HR, 1.24; 95% CI, 1.00 to 1.53 for high v low cHGF). Using partitioning analysis, we found that patients with elevated ctDNA combined with elevated cHGF constituted the highest risk group with significantly shorter OS. Conclusion Here, we report that BRIM-3 patients with high levels of ctDNA and cHGF have worse OS regardless of treatment and that these factors are independent prognostic markers for metastatic melanoma. .
Turajlic, S.
Xu, H.
Litchfield, K.
Rowan, A.
Horswell, S.
Chambers, T.
O'Brien, T.
Lopez, J.I.
Watkins, T.B.
Nicol, D.
Stares, M.
Challacombe, B.
Hazell, S.
Chandra, A.
Mitchell, T.J.
Au, L.
Eichler-Jonsson, C.
Jabbar, F.
Soultati, A.
Chowdhury, S.
Rudman, S.
Lynch, J.
Fernando, A.
Stamp, G.
Nye, E.
Stewart, A.
Xing, W.
Smith, J.C.
Escudero, M.
Huffman, A.
Matthews, N.
Elgar, G.
Phillimore, B.
Costa, M.
Begum, S.
Ward, S.
Salm, M.
Boeing, S.
Fisher, R.
Spain, L.
Navas, C.
Grönroos, E.
Hobor, S.
Sharma, S.
Aurangzeb, I.
Lall, S.
Polson, A.
Varia, M.
Horsfield, C.
Fotiadis, N.
Pickering, L.
Schwarz, R.F.
Silva, B.
Herrero, J.
Luscombe, N.M.
Jamal-Hanjani, M.
Rosenthal, R.
Birkbak, N.J.
Wilson, G.A.
Pipek, O.
Ribli, D.
Krzystanek, M.
Csabai, I.
Szallasi, Z.
Gore, M.
McGranahan, N.
Van Loo, P.
Campbell, P.
Larkin, J.
Swanton, C.
TRACERx Renal Consortium,
(2018). Deterministic Evolutionary Trajectories Influence Primary Tumor Growth: TRACERx Renal. Cell,
Vol.173
(3),
pp. 595-610.e11.
show abstract
The evolutionary features of clear-cell renal cell carcinoma (ccRCC) have not been systematically studied to date. We analyzed 1,206 primary tumor regions from 101 patients recruited into the multi-center prospective study, TRACERx Renal. We observe up to 30 driver events per tumor and show that subclonal diversification is associated with known prognostic parameters. By resolving the patterns of driver event ordering, co-occurrence, and mutual exclusivity at clone level, we show the deterministic nature of clonal evolution. ccRCC can be grouped into seven evolutionary subtypes, ranging from tumors characterized by early fixation of multiple mutational and copy number drivers and rapid metastases to highly branched tumors with >10 subclonal drivers and extensive parallel evolution associated with attenuated progression. We identify genetic diversity and chromosomal complexity as determinants of patient outcome. Our insights reconcile the variable clinical behavior of ccRCC and suggest evolutionary potential as a biomarker for both intervention and surveillance..
Turajlic, S.
Xu, H.
Litchfield, K.
Rowan, A.
Chambers, T.
Lopez, J.I.
Nicol, D.
O'Brien, T.
Larkin, J.
Horswell, S.
Stares, M.
Au, L.
Jamal-Hanjani, M.
Challacombe, B.
Chandra, A.
Hazell, S.
Eichler-Jonsson, C.
Soultati, A.
Chowdhury, S.
Rudman, S.
Lynch, J.
Fernando, A.
Stamp, G.
Nye, E.
Jabbar, F.
Spain, L.
Lall, S.
Guarch, R.
Falzon, M.
Proctor, I.
Pickering, L.
Gore, M.
Watkins, T.B.
Ward, S.
Stewart, A.
DiNatale, R.
Becerra, M.F.
Reznik, E.
Hsieh, J.J.
Richmond, T.A.
Mayhew, G.F.
Hill, S.M.
McNally, C.D.
Jones, C.
Rosenbaum, H.
Stanislaw, S.
Burgess, D.L.
Alexander, N.R.
Swanton, C.
PEACE,
TRACERx Renal Consortium,
(2018). Tracking Cancer Evolution Reveals Constrained Routes to Metastases: TRACERx Renal. Cell,
Vol.173
(3),
pp. 581-594.e12.
show abstract
Clear-cell renal cell carcinoma (ccRCC) exhibits a broad range of metastatic phenotypes that have not been systematically studied to date. Here, we analyzed 575 primary and 335 metastatic biopsies across 100 patients with metastatic ccRCC, including two cases sampledat post-mortem. Metastatic competence was afforded by chromosome complexity, and we identify 9p loss as a highly selected event driving metastasis and ccRCC-related mortality (p = 0.0014). Distinct patterns of metastatic dissemination were observed, including rapid progression to multiple tissue sites seeded by primary tumors of monoclonal structure. By contrast, we observed attenuated progression in cases characterized by high primary tumor heterogeneity, with metastatic competence acquired gradually and initial progression to solitary metastasis. Finally, we observed early divergence of primitive ancestral clones and protracted latency of up to two decades as a feature of pancreatic metastases..
Hauschild, A.
Dummer, R.
Schadendorf, D.
Santinami, M.
Atkinson, V.
Mandalà, M.
Chiarion-Sileni, V.
Larkin, J.
Nyakas, M.
Dutriaux, C.
Haydon, A.
Robert, C.
Mortier, L.
Schachter, J.
Lesimple, T.
Plummer, R.
Dasgupta, K.
Haas, T.
Shilkrut, M.
Gasal, E.
Kefford, R.
Kirkwood, J.M.
Long, G.V.
(2018). Longer Follow-Up Confirms Relapse-Free Survival Benefit With Adjuvant Dabrafenib Plus Trametinib in Patients With Resected BRAF V600-Mutant Stage III Melanoma. Journal of clinical oncology : official journal of the american society of clinical oncology,
Vol.36
(35),
pp. 3441-3449.
show abstract
Purpose Dabrafenib plus trametinib improved relapse-free survival (RFS) versus placebo (hazard ratio [HR], 0.47; P < .001) in patients with resected BRAF V600-mutant stage III melanoma (BRF115532; COMBI-AD; ClinicalTrials.gov identifier: NCT01682083). We present an updated RFS analysis on the basis of extended study follow-up and a cure-rate model analysis to estimate the fraction of patients expected to remain relapse free long term.Methods In this phase III trial, patients with resected BRAF V600-mutant stage III melanoma were randomly assigned to 12 months of adjuvant dabrafenib plus trametinib versus placebo. We report updated RFS (primary end point) and distant metastasis-free survival. RFS was also analyzed by subgroups defined by baseline disease stage (American Joint Committee on Cancer 7th and 8th editions), nodal metastatic burden, and ulceration status. The fraction of patients who remained relapse free long term was estimated using a Weibull mixture cure-rate model.Results At median follow-up of 44 months (dabrafenib plus trametinib) and 42 months (placebo), 3- and 4-year RFS rates were 59% (95% CI, 55% to 64%) and 54% (95% CI, 49% to 59%) in the dabrafenib plus trametinib arm and 40% (95% CI, 35% to 45%) and 38% (95% CI, 34% to 44%) in the placebo arm, respectively (HR, 0.49; 95% CI, 0.40 to 0.59). Distant metastasis-free survival also favored dabrafenib plus trametinib (HR, 0.53; 95% CI, 0.42 to 0.67). The estimated cure rate was 54% (95% CI, 49% to 59%) in the dabrafenib plus trametinib arm compared with 37% (95% CI, 32% to 42%) in the placebo arm. Subgroup analysis of RFS demonstrated similar treatment benefit regardless of baseline factors, including disease stage, nodal metastatic burden, and ulceration.Conclusion Longer follow-up confirmed RFS benefit with dabrafenib plus trametinib. Subgroup analysis suggested that dabrafenib plus trametinib benefited patients regardless of baseline factors..
Grob, J.J.
Garbe, C.
Ascierto, P.
Larkin, J.
Dummer, R.
Schadendorf, D.
(2018). Adjuvant melanoma therapy with new drugs: should physicians continue to focus on metastatic disease or use it earlier in primary melanoma?. The lancet oncology,
Vol.19
(12),
pp. e720-e725.
Mitchell, T.J.
Turajlic, S.
Rowan, A.
Nicol, D.
Farmery, J.H.
O'Brien, T.
Martincorena, I.
Tarpey, P.
Angelopoulos, N.
Yates, L.R.
Butler, A.P.
Raine, K.
Stewart, G.D.
Challacombe, B.
Fernando, A.
Lopez, J.I.
Hazell, S.
Chandra, A.
Chowdhury, S.
Rudman, S.
Soultati, A.
Stamp, G.
Fotiadis, N.
Pickering, L.
Au, L.
Spain, L.
Lynch, J.
Stares, M.
Teague, J.
Maura, F.
Wedge, D.C.
Horswell, S.
Chambers, T.
Litchfield, K.
Xu, H.
Stewart, A.
Elaidi, R.
Oudard, S.
McGranahan, N.
Csabai, I.
Gore, M.
Futreal, P.A.
Larkin, J.
Lynch, A.G.
Szallasi, Z.
Swanton, C.
Campbell, P.J.
TRACERx Renal Consortium,
(2018). Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal. ,
Vol.173
(3),
pp. 611-623.e17.
show abstract
Clear cell renal cell carcinoma (ccRCC) is characterized by near-universal loss of the short arm of chromosome 3, deleting several tumor suppressor genes. We analyzed whole genomes from 95 biopsies across 33 patients with clear cell renal cell carcinoma. We find hotspots of point mutations in the 5' UTR of TERT, targeting a MYC-MAX-MAD1 repressor associated with telomere lengthening. The most common structural abnormality generates simultaneous 3p loss and 5q gain (36% patients), typically through chromothripsis. This event occurs in childhood or adolescence, generally as the initiating event that precedes emergence of the tumor's most recent common ancestor by years to decades. Similar genomic changes drive inherited ccRCC. Modeling differences in age incidence between inherited and sporadic cancers suggests that the number of cells with 3p loss capable of initiating sporadic tumors is no more than a few hundred. Early development of ccRCC follows well-defined evolutionary trajectories, offering opportunity for early intervention..
Proskorovsky, I.
Benedict, A.
Negrier, S.
Bargo, D.
Sandin, R.
Ramaswamy, K.
Desai, J.
Cappelleri, J.C.
Larkin, J.
(2018). Axitinib, cabozantinib, or everolimus in the treatment of prior sunitinib-treated patients with metastatic renal cell carcinoma: results of matching-adjusted indirect comparison analyses. ,
Vol.18
(1),
p. 1271.
show abstract
BACKGROUND: In the absence of head-to-head trials comparing axitinib with cabozantinib or everolimus, the aim of this study was to conduct an indirect comparison of their relative efficacy in patients with metastatic renal cell carcinoma (mRCC), using data from the AXIS and METEOR trials. METHODS: Progression-free survival (PFS) and overall survival (OS) in prior sunitinib-treated patients with mRCC were compared by conducting matching-adjusted indirect comparison (MAIC) analyses, including base-case and sensitivity analyses. Individual patient-level data from prior sunitinib-treated patients who received axitinib in AXIS were weighted to match published baseline characteristics of prior sunitinib-treated patients who received either cabozantinib or everolimus in METEOR. RESULTS: There was no statistically significant difference in PFS (aHR [adjusted hazard ratio] = 1.15 [CI: 0.82-1.63]) and OS (aHR = 1.00 [CI: 0.69-1.46]) between axitinib versus cabozantinib in the base-case analysis. In the sensitivity analysis, PFS (aHR = 1.39 [CI: 1.00-1.92]) and OS (aHR = 1.35 [CI: 0.95-1.92]) were shorter for axitinib compared with cabozantinib; however, the OS difference was not statistically significant. Axitinib was associated with significantly longer PFS compared with everolimus in the base-case (aHR = 0.53 [CI: 0.36-0.80]) and sensitivity analyses (aHR = 0.63 [CI: 0.45-0.88]), respectively. Results suggested an OS benefit for axitinib versus everolimus in base-case analyses (aHR = 0.63 [CI: 0.42-0.96]); however, the difference in OS in the sensitivity analysis was not statistically significant (aHR = 0.84 [CI: 0.59-1.18]). CONCLUSIONS: MAIC analyses suggest PFS and OS for axitinib and cabozantinib are dependent on the Memorial Sloan Kettering Cancer Center definition used; in the base-case analysis, there was no significant difference in PFS and OS between axitinib and cabozantinib. In the sensitivity analysis, PFS in favour of cabozantinib was significant; however, the trend for prolonged OS with cabozantinib was not significant. For axitinib and everolimus, MAIC analyses indicate patients treated with axitinib may have an improved PFS and OS benefit when compared to everolimus. Disparities between the base-case and sensitivity analyses in this study underscore the importance of adjusting for the differences in baseline characteristics and that naïve indirect comparisons are not appropriate..
Dréno, B.
Ascierto, P.A.
Atkinson, V.
Liszkay, G.
Maio, M.
Mandalà, M.
Demidov, L.
Stroyakovskiy, D.
Thomas, L.
de la Cruz-Merino, L.
Dutriaux, C.
Garbe, C.
Bartley, K.
Karagiannis, T.
Chang, I.
Rooney, I.
Koralek, D.O.
Larkin, J.
McArthur, G.A.
Ribas, A.
(2018). Health-related quality of life impact of cobimetinib in combination with vemurafenib in patients with advanced or metastatic BRAFV600 mutation-positive melanoma. ,
Vol.118
(6),
pp. 777-784.
show abstract
BACKGROUND: In the coBRIM study, cobimetinib plus vemurafenib (C+V) significantly improved survival outcomes vs placebo and vemurafenib (P+V) in patients with advanced/metastatic BRAFV600-mutated melanoma. An analysis of health-related quality of life (HRQOL) from coBRIM is reported. METHODS: Patients completing the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30) at baseline and ⩾1 time point thereafter constituted the analysis population. Change from baseline ⩾10 points was considered clinically meaningful. RESULTS: Mean baseline scores for all QLQ-C30 domains were similar between arms. Most on-treatment scores for QLQ-C30 domains were also comparable between arms. A transient deterioration in role function in cycle 1 day 15 (C1D15; -14.7 points) in the P+V arm and improvement in insomnia in the C+V arm at C2D15 (-12.4 points) was observed. Among patients who experienced a ⩾10-point change from baseline (responders), between-group differences were greatest for insomnia (16%), social functioning (10%), fatigue (9%) and pain (7%), all favouring C+V. Diarrhoea, photosensitivity reaction, pyrexia, and rash did not meaningfully affect global health status (GHS). Serous retinopathy was associated with a transient decrease in GHS at C1D15 assessment. CONCLUSIONS: In patients with advanced/metastatic BRAFV600-mutated melanoma, treatment with C+V maintained HRQOL compared with P+V, with superior efficacy..
Spain, L.
Walls, G.
Messiou, C.
Turajlic, S.
Gore, M.
Larkin, J.
(2017). Efficacy and toxicity of rechallenge with combination immune checkpoint blockade in metastatic melanoma: a case series. Cancer immunology, immunotherapy : cii,
Vol.66
(1),
pp. 113-117.
show abstract
Background The efficacy and potential toxicity of rechallenge with combination ipilimumab and nivolumab has not been described. Retreatment of patients with immune checkpoint inhibitors in the setting of prior significant toxicity lacks evidence-based guidance.Methods We present the first three, consecutive patients who received re-treatment with combination ipilimumab and nivolumab for metastatic melanoma managed at our institution.Results Rechallenge with combination ipilimumab and nivolumab in the setting of prior grade 3 toxicity with initial combination therapy is feasible, and responses are seen. We highlight the fact that grade 3 toxicity is likely to recur, but if so, can be manageable.Conclusions Retreatment with ipi + nivo may be considered an option in carefully selected, well-informed patients. More research is required to delineate the benefits and risks with this approach..
Chapman, P.B.
Robert, C.
Larkin, J.
Haanen, J.B.
Ribas, A.
Hogg, D.
Hamid, O.
Ascierto, P.A.
Testori, A.
Lorigan, P.C.
Dummer, R.
Sosman, J.A.
Flaherty, K.T.
Chang, I.
Coleman, S.
Caro, I.
Hauschild, A.
McArthur, G.A.
(2017). Vemurafenib in patients with BRAFV600 mutation-positive metastatic melanoma: final overall survival results of the randomized BRIM-3 study. Ann oncol,
Vol.28
(10),
pp. 2581-2587.
show abstract
Background: The BRIM-3 trial showed improved progression-free survival (PFS) and overall survival (OS) for vemurafenib compared with dacarbazine in treatment-naive patients with BRAFV600 mutation-positive metastatic melanoma. We present final OS data from BRIM-3. Patients and methods: Patients were randomly assigned in a 1 : 1 ratio to receive vemurafenib (960 mg twice daily) or dacarbazine (1000 mg/m2 every 3 weeks). OS and PFS were co-primary end points. OS was assessed in the intention-to-treat population, with and without censoring of data for dacarbazine patients who crossed over to vemurafenib. Results: Between 4 January 2010 and 16 December 2010, a total of 675 patients were randomized to vemurafenib (n = 337) or dacarbazine (n = 338, of whom 84 crossed over to vemurafenib). At the time of database lock (14 August 2015), median OS, censored at crossover, was significantly longer for vemurafenib than for dacarbazine {13.6 months [95% confidence interval (CI) 12.0-15.4] versus 9.7 months [95% CI 7.9-12.8; hazard ratio (HR) 0.81 [95% CI 0.67-0.98]; P = 0.03}, as was median OS without censoring at crossover [13.6 months (95% CI 12.0-15.4) versus 10.3 months (95% CI 9.1-12.8); HR 0.81 (95% CI 0.68-0.96); P = 0.01]. Kaplan-Meier estimates of OS rates for vemurafenib versus dacarbazine were 56% versus 46%, 30% versus 24%, 21% versus 19% and 17% versus 16% at 1, 2, 3 and 4 years, respectively. Overall, 173 of the 338 patients (51%) in the dacarbazine arm and 175 of the 337 (52%) of those in the vemurafenib arm received subsequent anticancer therapies, most commonly ipilimumab. Safety data were consistent with the primary analysis. Conclusions: Vemurafenib continues to be associated with improved median OS in the BRIM-3 trial after extended follow-up. OS curves converged after ≈3 years, likely as a result of crossover from dacarbazine to vemurafenib and receipt of subsequent anticancer therapies. ClinicalTrials.gov: NCT01006980..
D'Angelo, S.P.
Larkin, J.
Sosman, J.A.
Lebbé, C.
Brady, B.
Neyns, B.
Schmidt, H.
Hassel, J.C.
Hodi, F.S.
Lorigan, P.
Savage, K.J.
Miller, W.H.
Mohr, P.
Marquez-Rodas, I.
Charles, J.
Kaatz, M.
Sznol, M.
Weber, J.S.
Shoushtari, A.N.
Ruisi, M.
Jiang, J.
Wolchok, J.D.
(2017). Efficacy and Safety of Nivolumab Alone or in Combination With Ipilimumab in Patients With Mucosal Melanoma: A Pooled Analysis. Journal of clinical oncology : official journal of the american society of clinical oncology,
Vol.35
(2),
pp. 226-235.
show abstract
Purpose Mucosal melanoma is an aggressive malignancy with a poor response to conventional therapies. The efficacy and safety of nivolumab (a programmed death-1 checkpoint inhibitor), alone or combined with ipilimumab (a cytotoxic T-lymphocyte antigen-4 checkpoint inhibitor), have not been reported in this rare melanoma subtype. Patients and Methods Data were pooled from 889 patients who received nivolumab monotherapy in clinical studies, including phase III trials; 86 (10%) had mucosal melanoma and 665 (75%) had cutaneous melanoma. Data were also pooled for patients who received nivolumab combined with ipilimumab (n = 35, mucosal melanoma; n = 326, cutaneous melanoma). Results Among patients who received nivolumab monotherapy, median progression-free survival was 3.0 months (95% CI, 2.2 to 5.4 months) and 6.2 months (95% CI, 5.1 to 7.5 months) for mucosal and cutaneous melanoma, with objective response rates of 23.3% (95% CI, 14.8% to 33.6%) and 40.9% (95% CI, 37.1% to 44.7%), respectively. Median progression-free survival in patients treated with nivolumab combined with ipilimumab was 5.9 months (95% CI, 2.8 months to not reached) and 11.7 months (95% CI, 8.9 to 16.7 months) for mucosal and cutaneous melanoma, with objective response rates of 37.1% (95% CI, 21.5% to 55.1%) and 60.4% (95% CI, 54.9% to 65.8%), respectively. For mucosal and cutaneous melanoma, respectively, the incidence of grade 3 or 4 treatment-related adverse events was 8.1% and 12.5% for nivolumab monotherapy and 40.0% and 54.9% for combination therapy. Conclusion To our knowledge, this is the largest analysis of data for anti-programmed death-1 therapy in mucosal melanoma to date. Nivolumab combined with ipilimumab seemed to have greater efficacy than either agent alone, and although the activity was lower in mucosal melanoma, the safety profile was similar between subtypes..
Bridgeman, V.L.
Vermeulen, P.B.
Foo, S.
Bilecz, A.
Daley, F.
Kostaras, E.
Nathan, M.R.
Wan, E.
Frentzas, S.
Schweiger, T.
Hegedus, B.
Hoetzenecker, K.
Renyi-Vamos, F.
Kuczynski, E.A.
Vasudev, N.S.
Larkin, J.
Gore, M.
Dvorak, H.F.
Paku, S.
Kerbel, R.S.
Dome, B.
Reynolds, A.R.
(2017). Vessel co-option is common in human lung metastases and mediates resistance to anti-angiogenic therapy in preclinical lung metastasis models. The journal of pathology,
Vol.241
(3),
pp. 362-374.
show abstract
Anti-angiogenic therapies have shown limited efficacy in the clinical management of metastatic disease, including lung metastases. Moreover, the mechanisms via which tumours resist anti-angiogenic therapies are poorly understood. Importantly, rather than utilizing angiogenesis, some metastases may instead incorporate pre-existing vessels from surrounding tissue (vessel co-option). As anti-angiogenic therapies were designed to target only new blood vessel growth, vessel co-option has been proposed as a mechanism that could drive resistance to anti-angiogenic therapy. However, vessel co-option has not been extensively studied in lung metastases, and its potential to mediate resistance to anti-angiogenic therapy in lung metastases is not established. Here, we examined the mechanism of tumour vascularization in 164 human lung metastasis specimens (composed of breast, colorectal and renal cancer lung metastasis cases). We identified four distinct histopathological growth patterns (HGPs) of lung metastasis (alveolar, interstitial, perivascular cuffing, and pushing), each of which vascularized via a different mechanism. In the alveolar HGP, cancer cells invaded the alveolar air spaces, facilitating the co-option of alveolar capillaries. In the interstitial HGP, cancer cells invaded the alveolar walls to co-opt alveolar capillaries. In the perivascular cuffing HGP, cancer cells grew by co-opting larger vessels of the lung. Only in the pushing HGP did the tumours vascularize by angiogenesis. Importantly, vessel co-option occurred with high frequency, being present in >80% of the cases examined. Moreover, we provide evidence that vessel co-option mediates resistance to the anti-angiogenic drug sunitinib in preclinical lung metastasis models. Assuming that our interpretation of the data is correct, we conclude that vessel co-option in lung metastases occurs through at least three distinct mechanisms, that vessel co-option occurs frequently in lung metastases, and that vessel co-option could mediate resistance to anti-angiogenic therapy in lung metastases. Novel therapies designed to target both angiogenesis and vessel co-option are therefore warranted. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland..
Spain, L.
Walls, G.
Julve, M.
O'Meara, K.
Schmid, T.
Kalaitzaki, E.
Turajlic, S.
Gore, M.
Rees, J.
Larkin, J.
(2017). Neurotoxicity from immune-checkpoint inhibition in the treatment of melanoma: a single centre experience and review of the literature. Annals of oncology : official journal of the european society for medical oncology,
Vol.28
(2),
pp. 377-385.
show abstract
Background Treatment with immune checkpoint inhibitors (ICPi) has greatly improved survival for patients with advanced melanoma in recent years. Anti-CTLA-4 and anti-PD1 antibodies have been approved following large Phase III trials. Immune-related neurological toxicity of varying severity has been reported in the literature. The cumulative incidence of neurotoxicity among ipilimumab, nivolumab and pembrolizumab is reported as <1% in published clinical trials. We aimed to identify the incidence of neurotoxicity in our institution across anti-CTLA4 and anti-PD-1 antibodies, including the combination of ipilimumab with nivolumab. We also review the existing literature and propose an investigation and management algorithm.Methods All patients with advanced melanoma treated with ipilimumab, nivolumab, pembrolizumab or the combination of ipilimumab and nivolumab (ipi + nivo), managed at the Royal Marsden Hospital between September 2010 and December 2015, including patients on (published) clinical trials were included. Medical records for each patient were reviewed and information on neurotoxicity recorded. A systematic search strategy was performed to collate existing reports of neurological toxicity.Results In total, 413 immunotherapy treatment episodes in 352 patients were included, with median follow-up of 26.7 months. Ten cases of neurotoxicity were recorded, affecting 2.8% of patients overall, ranging from grade 1 to 4, affecting both central and peripheral nervous systems. A rate of 14% was noted with ipi + nivo. Three of five patients commenced on corticosteroids responded to these. Six patients had made a full recovery at the time of reporting. A favorable radiological response was found in 7 of the 10 cases. Unusual presentations are described in detail.Conclusions Neurological toxicity is not uncommon, and may be more frequent in patients treated with combination ipi + nivo. Patterns of presentation and response to treatment are varied. A prompt and considered approach is required to optimize outcomes in this group of patients..
O'Reilly, A.
Larkin, J.
(2017). Lenvatinib for use in combination with everolimus for the treatment of patients with advanced renal cell carcinoma following one prior anti-angiogenic therapy. Expert review of clinical pharmacology,
Vol.10
(3),
pp. 251-262.
show abstract
Introduction In patients with mRCC options for second line therapies, following progression on anti-angiogenic agents, that demonstrate a survival advantage in clinical trials have been limited. Recently a number of agents have demonstrated efficacy in this setting. Here in we profile one such therapy, the combination of lenvatinib and everolimus, and discuss the expanded options for therapy available in this setting. Areas covered: In this review, we discuss current algorithms for treatment of mRCC in both the first-line and second-line setting. We discuss the recent addition of cabozantinib and nivolumab, in the second line setting, to the market. Lenvatinib's pharmacology, clinical efficacy and toxicity profile is discussed. A comprehensive literature review was performed using PUBMED. Expert commentary: The current treatment algorithms for mRCC will likely see significant change in the coming years. The addition of immunotherapy to our treatment options in mRCC is of particular importance. Future trials examining the use of immunotherapy, both as monotherapy and in combination with VEGF targeted therapy, will likely be a dominant influence in the therapeutic landscape of mRCC. Progress in terms of the rapid expansion of available active therapies in mRCC needs to be balanced with current deficiencies in terms of predictive biomarkers..
Bracarda, S.
Negrier, S.
Casper, J.
Porta, C.
Schmidinger, M.
Larkin, J.
Gross Goupil, M.
Escudier, B.
(2017). How clinical practice is changing the rules: the sunitinib 2/1 schedule in metastatic renal cell carcinoma. Expert review of anticancer therapy,
Vol.17
(3),
pp. 227-233.
show abstract
Introduction Currently, sunitinib is a standard of care in first-line treatment for metastatic renal cell carcinoma (mRCC). However, with the standard 4/2 schedule (sunitinib 50 mg/day; 4 consecutive weeks on treatment; 2 weeks' rest), 50% of patients require dose reductions to mitigate toxicity, highlighting the need to investigate alternative dosing schedules that improve tolerability without compromising efficacy. Areas covered: We present a concise critical review of published studies comparing the efficacy and safety of the 4/2 and 2/1 schedule (2 weeks on treatment; 1 week rest) for sunitinib. While all studies evaluating the 2/1 schedule have a low level of evidence, the results indicate that the 2/1 schedule improves tolerability compared with the 4/2 schedule, including significant reductions in the incidence of specific adverse events. It was not possible to make any definitive conclusions regarding efficacy due to methodologic limitations of these studies. Expert commentary: In the absence of strong evidence supporting the safety and efficacy of the 2/1 schedule, we recommend that patients should be initiated on sunitinib therapy with the standard 4/2 schedule and only be switched to the 2/1 schedule after the development of dose-limiting toxicities from weeks 3-4 (cycle 1) of the 4/2 schedule cycle..
Weber, J.S.
Hodi, F.S.
Wolchok, J.D.
Topalian, S.L.
Schadendorf, D.
Larkin, J.
Sznol, M.
Long, G.V.
Li, H.
Waxman, I.M.
Jiang, J.
Robert, C.
(2017). Safety Profile of Nivolumab Monotherapy: A Pooled Analysis of Patients With Advanced Melanoma. Journal of clinical oncology : official journal of the american society of clinical oncology,
Vol.35
(7),
pp. 785-792.
show abstract
Purpose We conducted a retrospective analysis to assess the safety profile of nivolumab monotherapy in patients with advanced melanoma and describe the management of adverse events (AEs) using established safety guidelines. Patients and Methods Safety data were pooled from four studies, including two phase III trials, with patients who received nivolumab 3 mg/kg once every 2 weeks. We evaluated rate of treatment-related AEs, time to onset and resolution of select AEs (those with potential immunologic etiology), and impact of select AEs and suppressive immune-modulating agents (IMs) on antitumor efficacy. Results Among 576 patients, 71% (95% CI, 67% to 75%) experienced any-grade treatment-related AEs (most commonly fatigue [25%], pruritus [17%], diarrhea [13%], and rash [13%]), and 10% (95% CI, 8% to 13%) experienced grade 3 to 4 treatment-related AEs. No drug-related deaths were reported. Select AEs (occurring in 49% of patients) were most frequently skin related, GI, endocrine, and hepatic; grade 3 to 4 select AEs occurred in 4% of patients. Median time to onset of select AEs ranged from 5 weeks for skin to 15 weeks for renal AEs. Approximately 24% of patients received systemic IMs to manage select AEs, which in most cases resolved. Adjusting for number of doses, objective response rate (ORR) was significantly higher in patients who experienced treatment-related select AEs of any grade compared with those who did not. ORRs were similar in patients who did and patients who did not receive systemic IMs. Conclusion Treatment-related AEs with nivolumab monotherapy were primarily low grade, and most resolved with established safety guidelines. Use of IMs did not affect ORR, although treatment-related select AEs of any grade were associated with higher ORR, but no progression-free survival benefit..
Morganstein, D.L.
Lai, Z.
Spain, L.
Diem, S.
Levine, D.
Mace, C.
Gore, M.
Larkin, J.
(2017). Thyroid abnormalities following the use of cytotoxic T-lymphocyte antigen-4 and programmed death receptor protein-1 inhibitors in the treatment of melanoma. Clinical endocrinology,
Vol.86
(4),
pp. 614-620.
show abstract
Context Checkpoint inhibitors are emerging as important cancer therapies but are associated with a high rate of immune side effects, including endocrinopathy.Objective To determine the burden of thyroid dysfunction in patients with melanoma treated with immune checkpoint inhibitors and describe the clinical course.Design and patients Consecutive patients with melanoma treated with either ipilimumab, nivolumab, pembrolizumab or the combination of ipilimumab and nivolumab were identified. Baseline thyroid function tests were used to exclude those with pre-existing thyroid abnormalities, and thyroid function tests during treatment used to identify those with thyroid dysfunction.Results Rates of overt thyroid dysfunction were in keeping with the published phase 3 trials. Hypothyroidism occurred in 13·0% treated with a programmed death receptor-1 (PD-1) inhibitor and 22·2% with a combination of PD-1 inhibitor and ipilimumab. Transient subclinical hyperthyroidism was observed in 13·0% treated with a PD-1 inhibitor, 15·9% following a PD-1 inhibitor, and 22·2% following combination treatment with investigations suggesting a thyroiditic mechanism rather than Graves' disease, and a high frequency of subsequent hypothyroidism. Any thyroid abnormality occurred in 23·0% following ipilimumab, 39·1% following a PD-1 inhibitor and 50% following combination treatment. Abnormal thyroid function was more common in female patients.Conclusion Thyroid dysfunction occurs commonly in patients with melanoma treated with immune checkpoint inhibitors, with rates, including subclinical dysfunction, occurring in up to 50%..
Spain, L.
Schmid, T.
Gore, M.
Larkin, J.
(2017). Efficacy of the combination of ipilimumab and nivolumab following progression on pembrolizumab in advanced melanoma with poor risk features. European journal of cancer (oxford, england : 1990),
Vol.75,
pp. 243-244.
Rothermundt, C.
von Rappard, J.
Eisen, T.
Escudier, B.
Grünwald, V.
Larkin, J.
McDermott, D.
Oldenburg, J.
Porta, C.
Rini, B.
Schmidinger, M.
Sternberg, C.N.
Putora, P.M.
(2017). Second-line treatment for metastatic clear cell renal cell cancer: experts' consensus algorithms. World journal of urology,
Vol.35
(4),
pp. 641-648.
show abstract
Background Second-line systemic treatment options for metastatic clear cell renal cell cancer (mccRCC) are diverse and treatment strategies are variable among experts. Our aim was to investigate the approach for the second-line treatment after first-line therapy with a tyrosine kinase inhibitor (TKI). Recently two phase III trials have demonstrated a potential role for nivolumab (NIV) and cabozantinib (CAB) in this setting. We aimed to estimate the impact of these trials on clinical decision making.Materials and methods Eleven international experts were asked to provide their treatment strategies for second-line systemic therapy for mccRCC in the current setting and once NIV and CAB will be approved and available. The treatment strategies were analyzed with the objective consensus approach.Results The analysis of the decision trees revealed everolimus (EVE), axitinib (AXI), NIV and TKI switch (sTKI) as therapeutic options after first-line TKI therapy in the current situation and mostly NIV and CAB in the future setting. The most commonly used criteria for treatment decisions were duration of response, TKI tolerance and zugzwang a composite of several related criteria.Conclusion In contrast to the first-line setting, recommendations for second-line systemic treatment of mccRCC among experts were not as heterogeneous. The agents mostly used after disease progression on a first-line TKI included: EVE, AXI, NIV and sTKI. In the future setting of NIV and CAB availability, NIV was the most commonly chosen drug, whereas several experts identified situations where CAB would be preferred..
Bowyer, S.
Prithviraj, P.
Lorigan, P.
Larkin, J.
McArthur, G.
Atkinson, V.
Millward, M.
Khou, M.
Diem, S.
Ramanujam, S.
Kong, B.
Liniker, E.
Guminski, A.
Parente, P.
Andrews, M.C.
Parakh, S.
Cebon, J.
Long, G.V.
Carlino, M.S.
Klein, O.
(2017). Reply to 'Comment on 'Efficacy and toxicity of treatment with the anti-CTLA-4 antibody ipilimumab in patients with metastatic melanoma after prior anti-PD-1 therapy''. British journal of cancer,
Vol.116
(8),
pp. e15-?.
Dréno, B.
Ribas, A.
Larkin, J.
Ascierto, P.A.
Hauschild, A.
Thomas, L.
Grob, J.-.
Koralek, D.O.
Rooney, I.
Hsu, J.J.
McKenna, E.F.
McArthur, G.A.
(2017). Incidence, course, and management of toxicities associated with cobimetinib in combination with vemurafenib in the coBRIM study. Annals of oncology : official journal of the european society for medical oncology,
Vol.28
(5),
pp. 1137-1144.
show abstract
Background In the coBRIM phase III trial, the addition of cobimetinib, an MEK inhibitor, to vemurafenib, a BRAF inhibitor, significantly improved progression-free survival [hazard ratio (HR), 0.58; P < 0.0001] and overall survival (HR, 0.70; P = 0.005) in advanced BRAF-mutated melanoma. Here, we report on the incidence, course, and management of key adverse events (AEs) in the coBRIM study.Patients and methods Patients were randomly assigned 1:1 to receive vemurafenib (960 mg twice a day) and either cobimetinib (60 mg once a day, 21 days on/7 days off) or placebo. In addition to standard safety evaluations, patients underwent regular ophthalmic, cardiac, and dermatologic surveillance examinations.Results Of 495 patients recruited to the study, 493 patients received treatment and constituted the safety population (cobimetinib combined with vemurafenib, 247; vemurafenib, 246). At data cut-off (30 September 2015), median follow-up was 18.5 months. Nearly every patient experienced an AE. In patients who received cobimetinib combined with vemurafenib, the frequency of grade ≥3 AEs was higher than in patients who received vemurafenib alone (75% versus 61%). Most AEs, including grade ≥3 AEs, occurred within the first treatment cycle. After the first cycle (28 days), the incidence of common AEs (rash, diarrhoea, photosensitivity, elevated creatine phosphokinase, serous retinopathy, pyrexia, and liver laboratory abnormalities) decreased substantially over time. Most AEs were managed conservatively by supportive care measures, dose modifications of study treatment, and, occasionally, permanent treatment discontinuation.Conclusions These data indicate that most AEs arising from treatment with cobimetinib combined with vemurafenib generally occur early in the treatment course, are mild or moderate and are manageable by patient monitoring, dose modification and supportive care.Clinicaltrials.gov NCT01689519..
Larkin, J.
Chmielowski, B.
Lao, C.D.
Hodi, F.S.
Sharfman, W.
Weber, J.
Suijkerbuijk, K.P.
Azevedo, S.
Li, H.
Reshef, D.
Avila, A.
Reardon, D.A.
(2017). Neurologic Serious Adverse Events Associated with Nivolumab Plus Ipilimumab or Nivolumab Alone in Advanced Melanoma, Including a Case Series of Encephalitis. The oncologist,
Vol.22
(6),
pp. 709-718.
show abstract
Background Despite unprecedented efficacy across multiple tumor types, immune checkpoint inhibitor therapy is associated with a unique and wide spectrum of immune-related adverse events (irAEs), including neurologic events ranging from mild headache to potentially life-threatening encephalitis. Here, we summarize neurologic irAEs associated with nivolumab and ipilimumab melanoma treatment, present cases of treatment-related encephalitis, and provide practical guidance on diagnosis and management.Methods We searched a Global Pharmacovigilance and Epidemiology database for neurologic irAEs reported over an 8-year period in patients with advanced melanoma receiving nivolumab with or without ipilimumab from 12 studies sponsored by Bristol-Myers Squibb. Serious neurologic irAEs were reviewed, and relationship to nivolumab or ipilimumab was assigned.Results In our search of 3,763 patients, 35 patients (0.93%) presented with 43 serious neurologic irAEs, including neuropathy ( n = 22), noninfective meningitis ( n = 5), encephalitis ( n = 6), neuromuscular disorders ( n = 3), and nonspecific adverse events ( n = 7). Study drug was discontinued ( n = 20), interrupted ( n = 8), or unchanged ( n = 7). Most neurologic irAEs resolved (26/35 patients; 75%). Overall, median time to onset was 45 days (range 1-170) and to resolution was 32 days (2-809+). Median time to onset of encephalitis was 55.5 days (range 18-297); four cases resolved and one was fatal.Conclusion Both oncologists and neurologists need to be aware of signs and symptoms of serious but uncommon neurologic irAEs associated with checkpoint inhibitors. Prompt diagnosis and management using an established algorithm are critical to minimize serious complications from these neurologic irAEs.Implications for practice With increasing use of checkpoint inhibitors in cancer, practicing oncologists need to be aware of the potential risk of neurologic immune-related adverse events and be able to provide prompt treatment of this uncommon, but potentially serious, class of adverse events. We summarize neurologic adverse events related to nivolumab alone or in combination with ipilimumab in patients with advanced melanoma from 12 studies and examine in depth 6 cases of encephalitis. We also provide input and guidance on the existing neurologic adverse events management algorithm for nivolumab and ipilimumab..
Stewart, G.D.
Aitchison, M.
Bex, A.
Larkin, J.
Lawless, C.
Méjean, A.
Nathan, P.
Oades, G.
Patard, J.-.
Paul, J.
Ravaud, A.
Escudier, B.
Renal Cross Channel Group,
(2017). Cytoreductive Nephrectomy in the Tyrosine Kinase Inhibitor Era: A Question That May Never Be Answered. European urology,
Vol.71
(6),
pp. 845-847.
show abstract
Despite great interest, two randomised controlled trials (RCTs) of cytoreductive nephrectomy in the tyrosine kinase inhibitor setting in metastatic renal cell carcinoma have either closed early (SURTIME) or are recruiting very slowly (CARMENA) after 7 yr. Challenges in RCT delivery in uro-oncologic surgery are many. Multiple steps are needed to ensure strong recruitment to trials addressing important urologic cancer questions. Feasibility/pilot studies are key stepping stones towards successful delivery of surgical RCTs..
O'reilly, A.
Larkin, J.
(2017). Checkpoint inhibitors in advanced melanoma: effect on the field of immunotherapy. Expert review of anticancer therapy,
Vol.17
(7),
pp. 647-655.
show abstract
Introduction The success of the immune checkpoint inhibitors in melanoma has reinvigorated the field of immunotherapy. Immune checkpoint inhibitors are now the standard of care in multiple cancer types including lung cancer, head and neck cancer, urothelial cancer and renal cell cancer. The field of immunotherapy is currently expanding rapidly and will be a focus of research and development for decades to come. Areas covered: This review covers the early development of immune checkpoint inhibitors and the changes that occurred in the drug development paradigm to facilitate the development of immunotherapy. The review will summarise the areas into which immune checkpoint inhibitors have been adopted and will review the data that supported this. Furthermore, we will discuss future developments in immunotherapy and the current landscape regarding maximising the potential of immunotherapy in clinical practice. Expert commentary: In the author's opinion, the potential of immunotherapy is vast. To date immune checkpoint inhibition has already delivered durable responses in a proportion of patients with cancer types which were previously universally lethal. The future of immunotherapy will rely upon the intelligent application of translational research to clinical practice, such that immunotherapy can be effective for a wider population and maintain its current growth..
Helgadottir, H.
Kis, L.
Ljungman, P.
Larkin, J.
Kefford, R.
Ascierto, P.A.
Hansson, J.
Masucci, G.
(2017). Lethal aplastic anemia caused by dual immune checkpoint blockade in metastatic melanoma. Annals of oncology : official journal of the european society for medical oncology,
Vol.28
(7),
pp. 1672-1673.
Blank, C.U.
Larkin, J.
Arance, A.M.
Hauschild, A.
Queirolo, P.
Del Vecchio, M.
Ascierto, P.A.
Krajsova, I.
Schachter, J.
Neyns, B.
Garbe, C.
Chiarion Sileni, V.
Mandalà, M.
Gogas, H.
Espinosa, E.
Hospers, G.A.
Miller, W.H.
Robson, S.
Makrutzki, M.
Antic, V.
Brown, M.P.
(2017). Open-label, multicentre safety study of vemurafenib in 3219 patients with BRAFV600 mutation-positive metastatic melanoma: 2-year follow-up data and long-term responders' analysis. European journal of cancer (oxford, england : 1990),
Vol.79,
pp. 176-184.
show abstract
Background The orally available BRAF kinase inhibitor vemurafenib is an effective and tolerable treatment option for patients with metastatic melanoma harbouring BRAF V600 mutations. We assessed the safety of vemurafenib in a large population of patients with few alternative treatment options; we report updated 2-year safety.Methods This was an open-label, multicentre study of vemurafenib (960 mg bid) in patients with previously treated or untreated BRAF mutation-positive metastatic melanoma (cobas ® 4800 BRAF V600 Mutation Test). The primary end-point was safety; efficacy end-points were secondary. An exploratory analysis was performed to assess safety outcomes in patients with long duration of response (DOR) (≥12 or ≥24 months).Results After a median follow-up of 32.2 months (95% CI, 31.1-33.2 months), 3079/3219 patients (96%) had discontinued treatment. Adverse events (AEs) were largely consistent with previous reports; the most common all-grade treatment-related AEs were arthralgia (37%), alopecia (25%) and hyperkeratosis (23%); the most common grade 3/4 treatment-related AEs were squamous cell carcinoma of the skin (8%) and keratoacanthoma (8%). In the exploratory analysis, patients with DOR ≥12 months (n = 287) or ≥24 months (n = 133) were more likely to experience grade 3/4 AEs than the overall population. No new specific safety signals were observed with longer vemurafenib exposure.Conclusions After 2 years' follow-up, safety was maintained in this large group of patients with BRAF V600 mutation-positive metastatic melanoma who are more representative of routine clinical practice than typical clinical trial populations. These data suggest that long-term vemurafenib treatment is effective and tolerable without the development of new safety signals..
Long, G.V.
Flaherty, K.T.
Stroyakovskiy, D.
Gogas, H.
Levchenko, E.
de Braud, F.
Larkin, J.
Garbe, C.
Jouary, T.
Hauschild, A.
Chiarion-Sileni, V.
Lebbe, C.
Mandalà, M.
Millward, M.
Arance, A.
Bondarenko, I.
Haanen, J.B.
Hansson, J.
Utikal, J.
Ferraresi, V.
Mohr, P.
Probachai, V.
Schadendorf, D.
Nathan, P.
Robert, C.
Ribas, A.
Davies, M.A.
Lane, S.R.
Legos, J.J.
Mookerjee, B.
Grob, J.-.
(2017). Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study. Annals of oncology : official journal of the european society for medical oncology,
Vol.28
(7),
pp. 1631-1639.
show abstract
Background Previous analysis of COMBI-d (NCT01584648) demonstrated improved progression-free survival (PFS) and overall survival (OS) with combination dabrafenib and trametinib versus dabrafenib monotherapy in BRAF V600E/K-mutant metastatic melanoma. This study was continued to assess 3-year landmark efficacy and safety after ≥36-month follow-up for all living patients.Patients and methods This double-blind, phase 3 study enrolled previously untreated patients with BRAF V600E/K-mutant unresectable stage IIIC or stage IV melanoma. Patients were randomized to receive dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) or dabrafenib plus placebo. The primary endpoint was PFS; secondary endpoints were OS, overall response, duration of response, safety, and pharmacokinetics.Results Between 4 May and 30 November 2012, a total of 423 of 947 screened patients were randomly assigned to receive dabrafenib plus trametinib (n = 211) or dabrafenib monotherapy (n = 212). At data cut-off (15 February 2016), outcomes remained superior with the combination: 3-year PFS was 22% with dabrafenib plus trametinib versus 12% with monotherapy, and 3-year OS was 44% versus 32%, respectively. Twenty-five patients receiving monotherapy crossed over to combination therapy, with continued follow-up under the monotherapy arm (per intent-to-treat principle). Of combination-arm patients alive at 3 years, 58% remained on dabrafenib plus trametinib. Three-year OS with the combination reached 62% in the most favourable subgroup (normal lactate dehydrogenase and <3 organ sites with metastasis) versus only 25% in the unfavourable subgroup (elevated lactate dehydrogenase). The dabrafenib plus trametinib safety profile was consistent with previous clinical trial observations, and no new safety signals were detected with long-term use.Conclusions These data demonstrate that durable (≥3 years) survival is achievable with dabrafenib plus trametinib in patients with BRAF V600-mutant metastatic melanoma and support long-term first-line use of the combination in this setting..
Colomba, E.
Le Teuff, G.
Eisen, T.
Stewart, G.D.
Fife, K.
Larkin, J.
Biondo, A.
Pickering, L.
Srinivasan, A.
Boyle, H.
Derosa, L.
Sternberg, C.N.
Recine, F.
Ralph, C.
Saldana, C.
Barthélémy, P.
Bernhard, J.C.
Gurney, H.
Verhoest, G.
Vauleon, E.
Bigot, P.
Berger, J.
Pfister, C.
Gravis, G.
Rodier, J.-.
Culine, S.
Caty, A.
Rolland, F.
Priou, F.
Escudier, B.
Albiges, L.
(2017). Metastatic chromophobe renal cell carcinoma treated with targeted therapies: A Renal Cross Channel Group study. European journal of cancer (oxford, england : 1990),
Vol.80,
pp. 55-62.
show abstract
Background Treatment of non-clear cell renal cell carcinoma (RCC) remains controversial despite several recent prospective studies of targeted therapies (TT). Often Vascular Endothelial growth Factor (VEGF) and Mammalian Target of Rapamycin (mTOR) inhibitors are used, extrapolating the data from use of these agents in clear cell RCC.Methods We performed a retrospective data analysis within the Renal Cross Channel Group to determine metastatic chromophobe RCC (mChRCC) outcomes in the TT era. The end-points were overall response, overall survival (OS) and time to treatment failure (TTF). The two latter were estimated using the Kaplan-Meier method.Results 91 mChRCC patients from 26 centres were included. Median follow-up from the date of first metastasis was 6.1 years (range: 0-13.9). Median OS was 37.9 months (95% confidence interval [CI]: 21.4-46.8) from the diagnosis of metastatic disease. Among the 61 patients who received TT, 50 (82%) were treated with anti-angiogenic (AA) and 11 with mTOR inhibitors. Median TTF and OS in patients receiving a first line of AA was 8.7 months (95% CI: 5.2-10.9) and 22.9 months (95% CI: 17.8-49.2) versus 1.9 months (95% CI: 1.0-6.0) and 3.2 months (95% CI: 2.3-not evaluable) with mTOR inhibitors, respectively. A stratified log-rank test was used to compare AA and mTOR inhibitors TT, while controlling the effect of the International Metastatic RCC Database Consortium risk group and no significant difference between AA and mTOR inhibitors was observed for TTF (p = 0.26) or for OS (p = 0.55).Conclusion We report the largest retrospective cohort of patients with mChRCC treated with TT and no significant difference between AA and mTOR inhibitors was observed for TTF and OS..
Haanen, J.B.
Carbonnel, F.
Robert, C.
Kerr, K.M.
Peters, S.
Larkin, J.
Jordan, K.
ESMO Guidelines Committee,
(2017). Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of oncology : official journal of the european society for medical oncology,
Vol.28
(suppl_4),
pp. iv119-iv142.
Turajlic, S.
Litchfield, K.
Xu, H.
Rosenthal, R.
McGranahan, N.
Reading, J.L.
Wong, Y.N.
Rowan, A.
Kanu, N.
Al Bakir, M.
Chambers, T.
Salgado, R.
Savas, P.
Loi, S.
Birkbak, N.J.
Sansregret, L.
Gore, M.
Larkin, J.
Quezada, S.A.
Swanton, C.
(2017). Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: a pan-cancer analysis. The lancet. oncology,
Vol.18
(8),
pp. 1009-1021.
show abstract
Background The focus of tumour-specific antigen analyses has been on single nucleotide variants (SNVs), with the contribution of small insertions and deletions (indels) less well characterised. We investigated whether the frameshift nature of indel mutations, which create novel open reading frames and a large quantity of mutagenic peptides highly distinct from self, might contribute to the immunogenic phenotype.Methods We analysed whole-exome sequencing data from 5777 solid tumours, spanning 19 cancer types from The Cancer Genome Atlas. We compared the proportion and number of indels across the cohort, with a subset of results replicated in two independent datasets. We assessed in-silico tumour-specific neoantigen predictions by mutation type with pan-cancer analysis, together with RNAseq profiling in renal clear cell carcinoma cases (n=392), to compare immune gene expression across patient subgroups. Associations between indel burden and treatment response were assessed across four checkpoint inhibitor datasets.Findings We observed renal cell carcinomas to have the highest proportion (0·12) and number of indel mutations across the pan-cancer cohort (p<2·2 × 10 -16 ), more than double the median proportion of indel mutations in all other cancer types examined. Analysis of tumour-specific neoantigens showed that enrichment of indel mutations for high-affinity binders was three times that of non-synonymous SNV mutations. Furthermore, neoantigens derived from indel mutations were nine times enriched for mutant specific binding, as compared with non-synonymous SNV derived neoantigens. Immune gene expression analysis in the renal clear cell carcinoma cohort showed that the presence of mutant-specific neoantigens was associated with upregulation of antigen presentation genes, which correlated (r=0·78) with T-cell activation as measured by CD8-positive expression. Finally, analysis of checkpoint inhibitor response data revealed frameshift indel count to be significantly associated with checkpoint inhibitor response across three separate melanoma cohorts (p=4·7 × 10 -4 ).Interpretation Renal cell carcinomas have the highest pan-cancer proportion and number of indel mutations. Evidence suggests indels are a highly immunogenic mutational class, which can trigger an increased abundance of neoantigens and greater mutant-binding specificity.Funding Cancer Research UK, UK National Institute for Health Research (NIHR) at the Royal Marsden Hospital National Health Service Foundation Trust, Institute of Cancer Research and University College London Hospitals Biomedical Research Centres, the UK Medical Research Council, the Rosetrees Trust, Novo Nordisk Foundation, the Prostate Cancer Foundation, the Breast Cancer Research Foundation, the European Research Council..
Matoori, S.
Thian, Y.
Koh, D.-.
Sohaib, A.
Larkin, J.
Pickering, L.
Gutzeit, A.
(2017). Contrast-Enhanced CT Density Predicts Response to Sunitinib Therapy in Metastatic Renal Cell Carcinoma Patients. Translational oncology,
Vol.10
(4),
pp. 679-685.
show abstract
The first-line therapy in metastatic renal cell carcinoma (mRCC), sunitinib, exhibits an objective response rate of approximately 30%. Therapeutic alternatives such as other tyrosine kinase inhibitors, VEGF inhibitors, or mTOR inhibitors emphasize the clinical need to predict the patient's response to sunitinib therapy before treatment initiation. In this study, we evaluated the prognostic value of pretreatment portal venous phase contrast-enhanced computed tomography (CECT) mean tumor density on overall survival (OS), progression-free survival (PFS), and tumor growth in 63 sunitinib-treated mRCC patients. Higher pretreatment CECT tumor density was associated with longer PFS and OS [hazard ratio (HR)=0.968, P=.002, and HR=0.956, P=.001, respectively], and CECT density was inversely correlated with tumor growth (P=.010). Receiver operating characteristic analysis identified two CECT density cut-off values (63.67 HU, sensitivity 0.704, specificity 0.694; and 68.67 HU, sensitivity 0.593, specificity 0.806) which yielded subpopulations with significantly different PFS and OS (P<.001). Pretreatment CECT is therefore a promising noninvasive strategy for response prediction in sunitinib-treated mRCC patients, identifying patients who will derive maximum therapeutic benefit..
O'Reilly, A.
Larkin, J.
(2017). The safety of nivolumab for the treatment of metastatic melanoma. Expert opinion on drug safety,
Vol.16
(8),
pp. 955-961.
show abstract
Introduction Nivolumab, a human IgG4 monoclonal antibody directed against PD-1, is a checkpoint inhibitor that is licenced in the treatment of metastatic melanoma either as a monotherapy or in combination with ipilimumab, a CTLA-4 inhibitor. The introduction of immune checkpoint inhibitors to the therapeutic landscape has dramatically altered outcomes in a proportion of patients with metastatic melanoma. Immune checkpoint inhibitors result in a toxicity profile that is distinct from that of chemotherapy or targeted therapy based on their immunomodulatory mechanism and similarly can result in patterns of response that are unique. Areas covered: Herein we will profile nivolumab's efficacy and safety both as a combination therapy and a monotherapy and discuss the results of relevant clinical trials in this respect. Expert opinion: The future of immunotherapy in melanoma will evolve around the development of biomarkers, the refinement of criteria to define patterns of response and toxicity and the combination of current immunotherapies with existing and novel agents to maximise responses..
Wongchenko, M.J.
McArthur, G.A.
Dréno, B.
Larkin, J.
Ascierto, P.A.
Sosman, J.
Andries, L.
Kockx, M.
Hurst, S.D.
Caro, I.
Rooney, I.
Hegde, P.S.
Molinero, L.
Yue, H.
Chang, I.
Amler, L.
Yan, Y.
Ribas, A.
(2017). Gene Expression Profiling in BRAF-Mutated Melanoma Reveals Patient Subgroups with Poor Outcomes to Vemurafenib That May Be Overcome by Cobimetinib Plus Vemurafenib. Clinical cancer research : an official journal of the american association for cancer research,
Vol.23
(17),
pp. 5238-5245.
show abstract
Purpose: The association of tumor gene expression profiles with progression-free survival (PFS) outcomes in patients with BRAFV600-mutated melanoma treated with vemurafenib or cobimetinib combined with vemurafenib was evaluated.Experimental Design: Gene expression of archival tumor samples from patients in four trials (BRIM-2, BRIM-3, BRIM-7, and coBRIM) was evaluated. Genes significantly associated with PFS (P < 0.05) were identified by univariate Cox proportional hazards modeling, then subjected to unsupervised hierarchical clustering, principal component analysis, and recursive partitioning to develop optimized gene signatures.Results: Forty-six genes were identified as significantly associated with PFS in both BRIM-2 (n = 63) and the vemurafenib arm of BRIM-3 (n = 160). Two distinct signatures were identified: cell cycle and immune. Among vemurafenib-treated patients, the cell-cycle signature was associated with shortened PFS compared with the immune signature in the BRIM-2/BRIM-3 training set [hazard ratio (HR) 1.8; 95% confidence interval (CI), 1.3-2.6, P = 0.0001] and in the coBRIM validation set (n = 101; HR, 1.6; 95% CI, 1.0-2.5; P = 0.08). The adverse impact of the cell-cycle signature on PFS was not observed in patients treated with cobimetinib combined with vemurafenib (n = 99; HR, 1.1; 95% CI, 0.7-1.8; P = 0.66).Conclusions: In vemurafenib-treated patients, the cell-cycle gene signature was associated with shorter PFS. However, in cobimetinib combined with vemurafenib-treated patients, both cell cycle and immune signature subgroups had comparable PFS. Cobimetinib combined with vemurafenib may abrogate the adverse impact of the cell-cycle signature. Clin Cancer Res; 23(17); 5238-45. ©2017 AACR..
Scelo, G.
Purdue, M.P.
Brown, K.M.
Johansson, M.
Wang, Z.
Eckel-Passow, J.E.
Ye, Y.
Hofmann, J.N.
Choi, J.
Foll, M.
Gaborieau, V.
Machiela, M.J.
Colli, L.M.
Li, P.
Sampson, J.N.
Abedi-Ardekani, B.
Besse, C.
Blanche, H.
Boland, A.
Burdette, L.
Chabrier, A.
Durand, G.
Le Calvez-Kelm, F.
Prokhortchouk, E.
Robinot, N.
Skryabin, K.G.
Wozniak, M.B.
Yeager, M.
Basta-Jovanovic, G.
Dzamic, Z.
Foretova, L.
Holcatova, I.
Janout, V.
Mates, D.
Mukeriya, A.
Rascu, S.
Zaridze, D.
Bencko, V.
Cybulski, C.
Fabianova, E.
Jinga, V.
Lissowska, J.
Lubinski, J.
Navratilova, M.
Rudnai, P.
Szeszenia-Dabrowska, N.
Benhamou, S.
Cancel-Tassin, G.
Cussenot, O.
Baglietto, L.
Boeing, H.
Khaw, K.-.
Weiderpass, E.
Ljungberg, B.
Sitaram, R.T.
Bruinsma, F.
Jordan, S.J.
Severi, G.
Winship, I.
Hveem, K.
Vatten, L.J.
Fletcher, T.
Koppova, K.
Larsson, S.C.
Wolk, A.
Banks, R.E.
Selby, P.J.
Easton, D.F.
Pharoah, P.
Andreotti, G.
Freeman, L.E.
Koutros, S.
Albanes, D.
Männistö, S.
Weinstein, S.
Clark, P.E.
Edwards, T.L.
Lipworth, L.
Gapstur, S.M.
Stevens, V.L.
Carol, H.
Freedman, M.L.
Pomerantz, M.M.
Cho, E.
Kraft, P.
Preston, M.A.
Wilson, K.M.
Michael Gaziano, J.
Sesso, H.D.
Black, A.
Freedman, N.D.
Huang, W.-.
Anema, J.G.
Kahnoski, R.J.
Lane, B.R.
Noyes, S.L.
Petillo, D.
Teh, B.T.
Peters, U.
White, E.
Anderson, G.L.
Johnson, L.
Luo, J.
Buring, J.
Lee, I.-.
Chow, W.-.
Moore, L.E.
Wood, C.
Eisen, T.
Henrion, M.
Larkin, J.
Barman, P.
Leibovich, B.C.
Choueiri, T.K.
Mark Lathrop, G.
Rothman, N.
Deleuze, J.-.
McKay, J.D.
Parker, A.S.
Wu, X.
Houlston, R.S.
Brennan, P.
Chanock, S.J.
(2017). Genome-wide association study identifies multiple risk loci for renal cell carcinoma. Nature communications,
Vol.8,
pp. 15724-?.
show abstract
Previous genome-wide association studies (GWAS) have identified six risk loci for renal cell carcinoma (RCC). We conducted a meta-analysis of two new scans of 5,198 cases and 7,331 controls together with four existing scans, totalling 10,784 cases and 20,406 controls of European ancestry. Twenty-four loci were tested in an additional 3,182 cases and 6,301 controls. We confirm the six known RCC risk loci and identify seven new loci at 1p32.3 (rs4381241, P=3.1 × 10 -10 ), 3p22.1 (rs67311347, P=2.5 × 10 -8 ), 3q26.2 (rs10936602, P=8.8 × 10 -9 ), 8p21.3 (rs2241261, P=5.8 × 10 -9 ), 10q24.33-q25.1 (rs11813268, P=3.9 × 10 -8 ), 11q22.3 (rs74911261, P=2.1 × 10 -10 ) and 14q24.2 (rs4903064, P=2.2 × 10 -24 ). Expression quantitative trait analyses suggest plausible candidate genes at these regions that may contribute to RCC susceptibility..
Schadendorf, D.
Larkin, J.
Wolchok, J.
Hodi, F.S.
Chiarion-Sileni, V.
Gonzalez, R.
Rutkowski, P.
Grob, J.-.
Cowey, C.L.
Lao, C.
Wagstaff, J.
Callahan, M.K.
Postow, M.A.
Smylie, M.
Ferrucci, P.F.
Dummer, R.
Hill, A.
Taylor, F.
Sabater, J.
Walker, D.
Kotapati, S.
Abernethy, A.
Long, G.V.
(2017). Health-related quality of life results from the phase III CheckMate 067 study. European journal of cancer (oxford, england : 1990),
Vol.82,
pp. 80-91.
show abstract
Background Nivolumab, a monoclonal antibody of immune checkpoint programmed death 1 on T cells (PD-1), combined with ipilimumab, an immune checkpoint cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor, as combination therapy on the one hand and nivolumab as monotherapy on the other, have both demonstrated improved efficacy compared with ipilimumab alone in the CheckMate 067 study. However, the combination resulted in a higher frequency of grade 3/4 adverse events (AEs), which could result in diminished health-related quality of life (HRQoL). Here we report analyses of HRQoL for patients with advanced melanoma in clinical trial CheckMate 067.Patients and methods HRQoL was assessed at weeks 1 and 5 per 6-week cycle for the first 6 months, once every 6 weeks thereafter, and at two follow-up visits using the European Organization for Research and Treatment of Care Core Quality of Life Questionnaire and the EuroQoL Five Dimensions Questionnaire. In addition to the randomised population, patient subgroups, including BRAF mutation status, partial or complete response, treatment-related AEs of grade 3/4, and those who discontinued due to any reason and due to an AE, were investigated.Results Nivolumab and ipilimumab combination and nivolumab alone both maintained HRQoL, and no clinically meaningful deterioration was observed over time compared with ipilimumab. In addition, similar results were observed across patient subgroups, and no clinically meaningful changes in HRQoL were observed during follow-up visits for patients who discontinued due to any cause.Conclusion These results further support the clinical benefit of nivolumab monotherapy and nivolumab and ipilimumab combination therapy in patients with advanced melanoma. The finding that the difference in grade 3/4 AEs between the arms did not translate into clinically meaningful differences in the reported HRQoL may be relevant in the clinical setting.Study number NCT01844505..
Ugurel, S.
Röhmel, J.
Ascierto, P.A.
Flaherty, K.T.
Grob, J.J.
Hauschild, A.
Larkin, J.
Long, G.V.
Lorigan, P.
McArthur, G.A.
Ribas, A.
Robert, C.
Schadendorf, D.
Garbe, C.
(2017). Survival of patients with advanced metastatic melanoma: the impact of novel therapies-update 2017. European journal of cancer (oxford, england : 1990),
Vol.83,
pp. 247-257.
show abstract
The treatment of metastatic melanoma is still undergoing a process of major change. The two most important novel therapeutic strategies, selective kinase inhibitors and immune checkpoint blockers, both significantly prolong survival times of patients with advanced metastatic disease. Different agents, dose regimens and combinations have been tested against each other vigorously within these two groups. However, results from prospective head-to-head comparative studies of both strategies are still lacking. We performed an exploratory analysis of survival data from selected clinical trials representative for the new treatment strategies in advanced metastatic melanoma. Eighty-three Kaplan-Meier survival curves from 25 trials were digitised and grouped by therapeutic strategy and treatment line. For each of these groups, mean survival curves were generated for progression-free (PFS) and overall survival (OS) by weighted averaging. Survival curves grouped together by therapeutic strategy revealed a high concordance, particularly in the first-line setting. For kinase inhibitors, the most favourable PFS and OS in all therapy lines were observed for combined BRAF plus MEK inhibition. For immune checkpoint inhibitors, combined PD-1 plus CTLA-4 inhibition demonstrated the best survival outcome in all categories except for OS in first-line therapy. For the latter, combined PD-1 plus CTLA-4 inhibition showed similar outcomes as single-agent PD-1 inhibition. Comparison of kinase inhibitors and checkpoint blockers revealed a superiority of combined BRAF plus MEK inhibition within the first 6 months, later changing to a superiority of PD-1 blockers alone or in combination with CTLA-4 blockers. These results need confirmation by prospective clinical trials..
Hsieh, J.J.
Purdue, M.P.
Signoretti, S.
Swanton, C.
Albiges, L.
Schmidinger, M.
Heng, D.Y.
Larkin, J.
Ficarra, V.
(2017). Renal cell carcinoma. Nature reviews. disease primers,
Vol.3,
pp. 17009-?.
show abstract
Renal cell carcinoma (RCC) denotes cancer originated from the renal epithelium and accounts for >90% of cancers in the kidney. The disease encompasses >10 histological and molecular subtypes, of which clear cell RCC (ccRCC) is most common and accounts for most cancer-related deaths. Although somatic VHL mutations have been described for some time, more-recent cancer genomic studies have identified mutations in epigenetic regulatory genes and demonstrated marked intra-tumour heterogeneity, which could have prognostic, predictive and therapeutic relevance. Localized RCC can be successfully managed with surgery, whereas metastatic RCC is refractory to conventional chemotherapy. However, over the past decade, marked advances in the treatment of metastatic RCC have been made, with targeted agents including sorafenib, sunitinib, bevacizumab, pazopanib and axitinib, which inhibit vascular endothelial growth factor (VEGF) and its receptor (VEGFR), and everolimus and temsirolimus, which inhibit mechanistic target of rapamycin complex 1 (mTORC1), being approved. Since 2015, agents with additional targets aside from VEGFR have been approved, such as cabozantinib and lenvatinib; immunotherapies, such as nivolumab, have also been added to the armamentarium for metastatic RCC. Here, we provide an overview of the biology of RCC, with a focus on ccRCC, as well as updates to complement the current clinical guidelines and an outline of potential future directions for RCC research and therapy..
Schachter, J.
Ribas, A.
Long, G.V.
Arance, A.
Grob, J.-.
Mortier, L.
Daud, A.
Carlino, M.S.
McNeil, C.
Lotem, M.
Larkin, J.
Lorigan, P.
Neyns, B.
Blank, C.
Petrella, T.M.
Hamid, O.
Zhou, H.
Ebbinghaus, S.
Ibrahim, N.
Robert, C.
(2017). Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet (london, england),
Vol.390
(10105),
pp. 1853-1862.
show abstract
Background Interim analyses of the phase 3 KEYNOTE-006 study showed superior overall and progression-free survival of pembrolizumab versus ipilimumab in patients with advanced melanoma. We present the final protocol-specified survival analysis.Methods In this multicentre, open-label, randomised, phase 3 trial, we recruited patients from 87 academic institutions, hospitals, and cancer centres in 16 countries (Australia, Austria, Belgium, Canada, Chile, Colombia, France, Germany, Israel, Netherlands, New Zealand, Norway, Spain, Sweden, UK, and USA). We randomly assigned participants (1:1:1) to one of two dose regimens of pembrolizumab, or one regimen of ipilimumab, using a centralised, computer-generated allocation schedule. Treatment assignments used blocked randomisation within strata. Eligible patients were at least 18 years old, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, at least one measurable lesion per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), unresectable stage III or IV melanoma (excluding ocular melanoma), and up to one previous systemic therapy (excluding anti-CTLA-4, PD-1, or PD-L1 agents). Secondary eligibility criteria are described later. Patients were excluded if they had active brain metastases or active autoimmune disease requiring systemic steroids. The primary outcome was overall survival (defined as the time from randomisation to death from any cause). Response was assessed per RECIST v1.1 by independent central review at week 12, then every 6 weeks up to week 48, and then every 12 weeks thereafter. Survival was assessed every 12 weeks, and final analysis occurred after all patients were followed up for at least 21 months. Primary analysis was done on the intention-to-treat population (all randomly assigned patients) and safety analyses were done in the treated population (all randomly assigned patients who received at least one dose of study treatment). Data cutoff date for this analysis was Dec 3, 2015. This study was registered with ClinicalTrials.gov, number NCT01866319.Findings Between Sept 18, 2013, and March 3, 2014, 834 patients with advanced melanoma were enrolled and randomly assigned to receive intravenous pembrolizumab every 2 weeks (n=279), intravenous pembrolizumab every 3 weeks (n=277), or intravenous ipilimumab every 3 weeks (ipilimumab for four doses; n=278). One patient in the pembrolizumab 2 week group and 22 patients in the ipilimumab group withdrew consent and did not receive treatment. A total of 811 patients received at least one dose of study treatment. Median follow-up was 22·9 months; 383 patients died. Median overall survival was not reached in either pembrolizumab group and was 16·0 months with ipilimumab (hazard ratio [HR] 0·68, 95% CI 0·53-0·87 for pembrolizumab every 2 weeks vs ipilimumab; p=0·0009 and 0·68, 0·53-0·86 for pembrolizumab every 3 weeks vs ipilimumab; p=0·0008). 24-month overall survival rate was 55% in the 2-week group, 55% in the 3-week group, and 43% in the ipilimumab group.Interpretation Substantiating the results of the interim analyses of KEYNOTE-006, pembrolizumab continued to provide superior overall survival versus ipilimumab, with no difference between pembrolizumab dosing schedules. These conclusions further support the use of pembrolizumab as a standard of care for advanced melanoma.Funding Merck & Co..
Flynn, M.J.
Larkin, J.M.
(2017). Novel combination strategies for enhancing efficacy of immune checkpoint inhibitors in the treatment of metastatic solid malignancies. Expert opinion on pharmacotherapy,
Vol.18
(14),
pp. 1477-1490.
show abstract
Introduction Immune-checkpoint inhibitor (ICPI) drugs, which include antibodies against CTLA-4, PD-1 and PD-L1, have been shown to induce durable complete responses in a proportion of patients with particular efficacy demonstrated in both the first line and refractory setting in advanced NSCLC and melanoma. However, these drugs remain effective only in a minority of unselected patients. Areas covered: This review will focus on mechanisms of resistance to ICPI and underline the importance of identification of novel predictive markers of responsiveness. The rationale for the combination of ICPI with specific chemotherapies, targeted therapies and other immuno-oncology drugs in order to improve efficacy will be provided. Expert opinion: There are near-endless permutations of combination strategies of these agents with ICPI that have become feasible treatment strategies. Development of an understanding of resistance mechanisms to ICPI by a shift towards translational approaches to comprehensive genomic profiling and interrogation of the tumor microenvironment will encourage recruitment of patients into biomarker-driven combination trials. More than ever, industry professionals, clinicians and scientists will need to collaborate to increase the investment in clinical trials of those therapeutic agents and combination strategies which are most likely to be transformative for patients..
Wolchok, J.D.
Chiarion-Sileni, V.
Gonzalez, R.
Rutkowski, P.
Grob, J.-.
Cowey, C.L.
Lao, C.D.
Wagstaff, J.
Schadendorf, D.
Ferrucci, P.F.
Smylie, M.
Dummer, R.
Hill, A.
Hogg, D.
Haanen, J.
Carlino, M.S.
Bechter, O.
Maio, M.
Marquez-Rodas, I.
Guidoboni, M.
McArthur, G.
Lebbé, C.
Ascierto, P.A.
Long, G.V.
Cebon, J.
Sosman, J.
Postow, M.A.
Callahan, M.K.
Walker, D.
Rollin, L.
Bhore, R.
Hodi, F.S.
Larkin, J.
(2017). Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. The new england journal of medicine,
Vol.377
(14),
pp. 1345-1356.
show abstract
Background Nivolumab combined with ipilimumab resulted in longer progression-free survival and a higher objective response rate than ipilimumab alone in a phase 3 trial involving patients with advanced melanoma. We now report 3-year overall survival outcomes in this trial.Methods We randomly assigned, in a 1:1:1 ratio, patients with previously untreated advanced melanoma to receive nivolumab at a dose of 1 mg per kilogram of body weight plus ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses, followed by nivolumab at a dose of 3 mg per kilogram every 2 weeks; nivolumab at a dose of 3 mg per kilogram every 2 weeks plus placebo; or ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses plus placebo, until progression, the occurrence of unacceptable toxic effects, or withdrawal of consent. Randomization was stratified according to programmed death ligand 1 (PD-L1) status, BRAF mutation status, and metastasis stage. The two primary end points were progression-free survival and overall survival in the nivolumab-plus-ipilimumab group and in the nivolumab group versus the ipilimumab group.Results At a minimum follow-up of 36 months, the median overall survival had not been reached in the nivolumab-plus-ipilimumab group and was 37.6 months in the nivolumab group, as compared with 19.9 months in the ipilimumab group (hazard ratio for death with nivolumab plus ipilimumab vs. ipilimumab, 0.55 [P<0.001]; hazard ratio for death with nivolumab vs. ipilimumab, 0.65 [P<0.001]). The overall survival rate at 3 years was 58% in the nivolumab-plus-ipilimumab group and 52% in the nivolumab group, as compared with 34% in the ipilimumab group. The safety profile was unchanged from the initial report. Treatment-related adverse events of grade 3 or 4 occurred in 59% of the patients in the nivolumab-plus-ipilimumab group, in 21% of those in the nivolumab group, and in 28% of those in the ipilimumab group.Conclusions Among patients with advanced melanoma, significantly longer overall survival occurred with combination therapy with nivolumab plus ipilimumab or with nivolumab alone than with ipilimumab alone. (Funded by Bristol-Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505 .)..
Arce Vargas, F.
Furness, A.J.
Solomon, I.
Joshi, K.
Mekkaoui, L.
Lesko, M.H.
Miranda Rota, E.
Dahan, R.
Georgiou, A.
Sledzinska, A.
Ben Aissa, A.
Franz, D.
Werner Sunderland, M.
Wong, Y.N.
Henry, J.Y.
O'Brien, T.
Nicol, D.
Challacombe, B.
Beers, S.A.
Melanoma TRACERx Consortium,
Renal TRACERx Consortium,
Lung TRACERx Consortium,
Turajlic, S.
Gore, M.
Larkin, J.
Swanton, C.
Chester, K.A.
Pule, M.
Ravetch, J.V.
Marafioti, T.
Peggs, K.S.
Quezada, S.A.
(2017). Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors. Immunity,
Vol.46
(4),
pp. 577-586.
show abstract
CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models. Use of an anti-CD25 antibody with enhanced binding to activating FcγRs led to effective depletion of tumor-infiltrating Treg cells, increased effector to Treg cell ratios, and improved control of established tumors. Combination with anti-programmed cell death protein-1 antibodies promoted complete tumor rejection, demonstrating the relevance of CD25 as a therapeutic target and promising substrate for future combination approaches in immune-oncology..
Long, G.V.
Weber, J.S.
Larkin, J.
Atkinson, V.
Grob, J.-.
Schadendorf, D.
Dummer, R.
Robert, C.
Márquez-Rodas, I.
McNeil, C.
Schmidt, H.
Briscoe, K.
Baurain, J.-.
Hodi, F.S.
Wolchok, J.D.
(2017). Nivolumab for Patients With Advanced Melanoma Treated Beyond Progression: Analysis of 2 Phase 3 Clinical Trials. Jama oncology,
Vol.3
(11),
pp. 1511-1519.
show abstract
Importance Immune checkpoint inhibitors have demonstrated atypical response patterns, which may not be fully captured by conventional response criteria. There is a need to better understand the potential benefit of continued immune checkpoint inhibition beyond progression.Objective To evaluate the safety and potential benefit of nivolumab (anti-programmed cell death receptor 1) monotherapy beyond Response Evaluation Criteria in Solid Tumors (RECIST) v1.1-defined progression.Design, setting, and participants Pooled, retrospective analysis of data from phase 3 trials of nivolumab in treatment-naive patients with advanced melanoma (CheckMate 066 or CheckMate 067) conducted at academic and clinical cancer centers. Participants were patients treated beyond first disease progression, defined as those who received their last dose of nivolumab more than 6 weeks after progression (TBP group); and patients not treated beyond progression, who discontinued nivolumab therapy before or at progression (non-TBP group). Data analyses were conducted from November 6, 2015, to January 11, 2017.Interventions Nivolumab (3 mg/kg every 2 weeks) administered until progression or unacceptable toxic effects. Patients could be treated beyond progression if deriving apparent clinical benefit and tolerating study drug, at the investigator's discretion.Main outcomes and measures Tumor response and safety in TBP and non-TBP patients.Results Among 526 randomized patients (39% [n = 203] female; median age, 62 years [range, 18-90 years]), 306 (58%) experienced disease progression, including 85 (28%) TBP patients and 221 (72%) non-TBP patients. Twenty-four (28%) of the TBP patients had a target lesion reduction of greater than 30% after progression compared with baseline (TBP>30% group). At the time of this analysis, 65 (76%) TBP patients and 21 (87%) TBP>30% patients were still alive; 27 (32%) and 11 (46%), respectively, continued to receive treatment. Median (range) time from progression to last dose of treatment was 4.7 (1.4-25.8) months for TBP patients and 7.6 (2.4-19.4) months for TBP>30% patients. Median (range) time from progression to greater than 30% tumor reduction was 1.4 (0.2-7.0) months. Treatment-related select grade 3 to 4 adverse events were similar in the TBP and non-TBP groups (5 [6%] and 9 [4%], respectively).Conclusions and relevance A substantial proportion of selected patients treated with frontline nivolumab who were clinically stable and judged to be eligible for treatment beyond RECIST v1.1-defined progression by the treating investigators derived apparent clinical benefit without compromising safety. Further analysis will help define the potential benefit of continued nivolumab treatment beyond progression.Trial registration clinicaltrials.gov Identifiers: NCT01721772 (CheckMate 066) and NCT01844505 (CheckMate 067)..
Machiela, M.J.
Hofmann, J.N.
Carreras-Torres, R.
Brown, K.M.
Johansson, M.
Wang, Z.
Foll, M.
Li, P.
Rothman, N.
Savage, S.A.
Gaborieau, V.
McKay, J.D.
Ye, Y.
Henrion, M.
Bruinsma, F.
Jordan, S.
Severi, G.
Hveem, K.
Vatten, L.J.
Fletcher, T.
Koppova, K.
Larsson, S.C.
Wolk, A.
Banks, R.E.
Selby, P.J.
Easton, D.F.
Pharoah, P.
Andreotti, G.
Freeman, L.E.
Koutros, S.
Albanes, D.
Mannisto, S.
Weinstein, S.
Clark, P.E.
Edwards, T.E.
Lipworth, L.
Gapstur, S.M.
Stevens, V.L.
Carol, H.
Freedman, M.L.
Pomerantz, M.M.
Cho, E.
Kraft, P.
Preston, M.A.
Wilson, K.M.
Gaziano, J.M.
Sesso, H.S.
Black, A.
Freedman, N.D.
Huang, W.-.
Anema, J.G.
Kahnoski, R.J.
Lane, B.R.
Noyes, S.L.
Petillo, D.
Colli, L.M.
Sampson, J.N.
Besse, C.
Blanche, H.
Boland, A.
Burdette, L.
Prokhortchouk, E.
Skryabin, K.G.
Yeager, M.
Mijuskovic, M.
Ognjanovic, M.
Foretova, L.
Holcatova, I.
Janout, V.
Mates, D.
Mukeriya, A.
Rascu, S.
Zaridze, D.
Bencko, V.
Cybulski, C.
Fabianova, E.
Jinga, V.
Lissowska, J.
Lubinski, J.
Navratilova, M.
Rudnai, P.
Szeszenia-Dabrowska, N.
Benhamou, S.
Cancel-Tassin, G.
Cussenot, O.
Bueno-de-Mesquita, H.B.
Canzian, F.
Duell, E.J.
Ljungberg, B.
Sitaram, R.T.
Peters, U.
White, E.
Anderson, G.L.
Johnson, L.
Luo, J.
Buring, J.
Lee, I.-.
Chow, W.-.
Moore, L.E.
Wood, C.
Eisen, T.
Larkin, J.
Choueiri, T.K.
Lathrop, G.M.
Teh, B.T.
Deleuze, J.-.
Wu, X.
Houlston, R.S.
Brennan, P.
Chanock, S.J.
Scelo, G.
Purdue, M.P.
(2017). Genetic Variants Related to Longer Telomere Length are Associated with Increased Risk of Renal Cell Carcinoma. European urology,
Vol.72
(5),
pp. 747-754.
show abstract
Background Relative telomere length in peripheral blood leukocytes has been evaluated as a potential biomarker for renal cell carcinoma (RCC) risk in several studies, with conflicting findings.Objective We performed an analysis of genetic variants associated with leukocyte telomere length to assess the relationship between telomere length and RCC risk using Mendelian randomization, an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations.Design, setting, and participants Genotypes from nine telomere length-associated variants for 10 784 cases and 20 406 cancer-free controls from six genome-wide association studies (GWAS) of RCC were aggregated into a weighted genetic risk score (GRS) predictive of leukocyte telomere length.Outcome measurements and statistical analysis Odds ratios (ORs) relating the GRS and RCC risk were computed in individual GWAS datasets and combined by meta-analysis.Results and limitations Longer genetically inferred telomere length was associated with an increased risk of RCC (OR=2.07 per predicted kilobase increase, 95% confidence interval [CI]:=1.70-2.53, p<0.0001). As a sensitivity analysis, we excluded two telomere length variants in linkage disequilibrium (R 2 >0.5) with GWAS-identified RCC risk variants (rs10936599 and rs9420907) from the telomere length GRS; despite this exclusion, a statistically significant association between the GRS and RCC risk persisted (OR=1.73, 95% CI=1.36-2.21, p<0.0001). Exploratory analyses for individual histologic subtypes suggested comparable associations with the telomere length GRS for clear cell (N=5573, OR=1.93, 95% CI=1.50-2.49, p<0.0001), papillary (N=573, OR=1.96, 95% CI=1.01-3.81, p=0.046), and chromophobe RCC (N=203, OR=2.37, 95% CI=0.78-7.17, p=0.13).Conclusions Our investigation adds to the growing body of evidence indicating some aspect of longer telomere length is important for RCC risk.Patient summary Telomeres are segments of DNA at chromosome ends that maintain chromosomal stability. Our study investigated the relationship between genetic variants associated with telomere length and renal cell carcinoma risk. We found evidence suggesting individuals with inherited predisposition to longer telomere length are at increased risk of developing renal cell carcinoma..
Long, G.V.
Hauschild, A.
Santinami, M.
Atkinson, V.
Mandalà, M.
Chiarion-Sileni, V.
Larkin, J.
Nyakas, M.
Dutriaux, C.
Haydon, A.
Robert, C.
Mortier, L.
Schachter, J.
Schadendorf, D.
Lesimple, T.
Plummer, R.
Ji, R.
Zhang, P.
Mookerjee, B.
Legos, J.
Kefford, R.
Dummer, R.
Kirkwood, J.M.
(2017). Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma. The new england journal of medicine,
Vol.377
(19),
pp. 1813-1823.
show abstract
Background Combination therapy with the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib improved survival in patients with advanced melanoma with BRAF V600 mutations. We sought to determine whether adjuvant dabrafenib plus trametinib would improve outcomes in patients with resected, stage III melanoma with BRAF V600 mutations.Methods In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 870 patients with completely resected, stage III melanoma with BRAF V600E or V600K mutations to receive oral dabrafenib at a dose of 150 mg twice daily plus trametinib at a dose of 2 mg once daily (combination therapy, 438 patients) or two matched placebo tablets (432 patients) for 12 months. The primary end point was relapse-free survival. Secondary end points included overall survival, distant metastasis-free survival, freedom from relapse, and safety.Results At a median follow-up of 2.8 years, the estimated 3-year rate of relapse-free survival was 58% in the combination-therapy group and 39% in the placebo group (hazard ratio for relapse or death, 0.47; 95% confidence interval [CI], 0.39 to 0.58; P<0.001). The 3-year overall survival rate was 86% in the combination-therapy group and 77% in the placebo group (hazard ratio for death, 0.57; 95% CI, 0.42 to 0.79; P=0.0006), but this level of improvement did not cross the prespecified interim analysis boundary of P=0.000019. Rates of distant metastasis-free survival and freedom from relapse were also higher in the combination-therapy group than in the placebo group. The safety profile of dabrafenib plus trametinib was consistent with that observed with the combination in patients with metastatic melanoma.Conclusions Adjuvant use of combination therapy with dabrafenib plus trametinib resulted in a significantly lower risk of recurrence in patients with stage III melanoma with BRAF V600E or V600K mutations than the adjuvant use of placebo and was not associated with new toxic effects. (Funded by GlaxoSmithKline and Novartis; COMBI-AD ClinicalTrials.gov, NCT01682083 ; EudraCT number, 2012-001266-15 .)..
Weber, J.
Mandala, M.
Del Vecchio, M.
Gogas, H.J.
Arance, A.M.
Cowey, C.L.
Dalle, S.
Schenker, M.
Chiarion-Sileni, V.
Marquez-Rodas, I.
Grob, J.-.
Butler, M.O.
Middleton, M.R.
Maio, M.
Atkinson, V.
Queirolo, P.
Gonzalez, R.
Kudchadkar, R.R.
Smylie, M.
Meyer, N.
Mortier, L.
Atkins, M.B.
Long, G.V.
Bhatia, S.
Lebbé, C.
Rutkowski, P.
Yokota, K.
Yamazaki, N.
Kim, T.M.
de Pril, V.
Sabater, J.
Qureshi, A.
Larkin, J.
Ascierto, P.A.
CheckMate 238 Collaborators,
(2017). Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. The new england journal of medicine,
Vol.377
(19),
pp. 1824-1835.
show abstract
Background Nivolumab and ipilimumab are immune checkpoint inhibitors that have been approved for the treatment of advanced melanoma. In the United States, ipilimumab has also been approved as adjuvant therapy for melanoma on the basis of recurrence-free and overall survival rates that were higher than those with placebo in a phase 3 trial. We wanted to determine the efficacy of nivolumab versus ipilimumab for adjuvant therapy in patients with resected advanced melanoma.Methods In this randomized, double-blind, phase 3 trial, we randomly assigned 906 patients (≥15 years of age) who were undergoing complete resection of stage IIIB, IIIC, or IV melanoma to receive an intravenous infusion of either nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks (453 patients) or ipilimumab at a dose of 10 mg per kilogram every 3 weeks for four doses and then every 12 weeks (453 patients). The patients were treated for a period of up to 1 year or until disease recurrence, a report of unacceptable toxic effects, or withdrawal of consent. The primary end point was recurrence-free survival in the intention-to-treat population.Results At a minimum follow-up of 18 months, the 12-month rate of recurrence-free survival was 70.5% (95% confidence interval [CI], 66.1 to 74.5) in the nivolumab group and 60.8% (95% CI, 56.0 to 65.2) in the ipilimumab group (hazard ratio for disease recurrence or death, 0.65; 97.56% CI, 0.51 to 0.83; P<0.001). Treatment-related grade 3 or 4 adverse events were reported in 14.4% of the patients in the nivolumab group and in 45.9% of those in the ipilimumab group; treatment was discontinued because of any adverse event in 9.7% and 42.6% of the patients, respectively. Two deaths (0.4%) related to toxic effects were reported in the ipilimumab group more than 100 days after treatment.Conclusions Among patients undergoing resection of stage IIIB, IIIC, or IV melanoma, adjuvant therapy with nivolumab resulted in significantly longer recurrence-free survival and a lower rate of grade 3 or 4 adverse events than adjuvant therapy with ipilimumab. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; CheckMate 238 ClinicalTrials.gov number, NCT02388906 ; Eudra-CT number, 2014-002351-26 .)..
Schadendorf, D.
Wolchok, J.D.
Hodi, F.S.
Chiarion-Sileni, V.
Gonzalez, R.
Rutkowski, P.
Grob, J.-.
Cowey, C.L.
Lao, C.D.
Chesney, J.
Robert, C.
Grossmann, K.
McDermott, D.
Walker, D.
Bhore, R.
Larkin, J.
Postow, M.A.
(2017). Efficacy and Safety Outcomes in Patients With Advanced Melanoma Who Discontinued Treatment With Nivolumab and Ipilimumab Because of Adverse Events: A Pooled Analysis of Randomized Phase II and III Trials. Journal of clinical oncology : official journal of the american society of clinical oncology,
Vol.35
(34),
pp. 3807-3814.
show abstract
Purpose Approximately 40% of patients with advanced melanoma who received nivolumab combined with ipilimumab in clinical trials discontinued treatment because of adverse events (AEs). We conducted a retrospective analysis to assess the efficacy and safety of nivolumab plus ipilimumab in patients who discontinued treatment because of AEs. Methods Data were pooled from phase II and III trials of patients who received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, every 3 weeks for four doses, followed by nivolumab monotherapy 3 mg/kg every 2 weeks (N = 409). Efficacy was assessed in all randomly assigned patients who discontinued because of AEs during the induction phase (n = 96) and in those who did not discontinue because of AEs (n = 233). Safety was assessed in treated patients who discontinued because of AEs (n = 176) at any time and in those who did not discontinue because of AEs (n = 231). Results At a minimum follow-up of 18 months, median progression-free survival was 8.4 months for patients who discontinued treatment because of AEs during the induction phase and 10.8 months for patients who did not discontinue because of AEs ( P = .97). Median overall survival had not been reached in either group ( P = .23). The objective response rate was 58.3% for patients who discontinued because of AEs during the induction phase and 50.2% for patients who did not discontinue. The vast majority of grade 3 or 4 AEs occurred during the induction phase, with most resolving after appropriate management. Conclusion Efficacy outcomes seemed similar between patients who discontinued nivolumab plus ipilimumab treatment because of AEs during the induction phase and those who did not discontinue because of AEs. Therefore, even after discontinuation, many patients may continue to derive benefit from combination therapy..
Grande, E.
Glen, H.
Aller, J.
Argenziano, G.
Lamas, M.J.
Ruszniewski, P.
Zamorano, J.L.
Edmonds, K.
Sarker, S.
Staehler, M.
Larkin, J.
(2017). Recommendations on managing lenvatinib and everolimus in patients with advanced or metastatic renal cell carcinoma. Expert opinion on drug safety,
Vol.16
(12),
pp. 1413-1426.
show abstract
Introduction There are several second-line treatment options for patients with renal cell carcinoma after first-line failure of a tyrosine kinase inhibitor, especially with the recent approvals of cabozantinib, nivolumab, and the lenvatinib plus everolimus combination. A lack of reliable biomarkers and an overall lack of prospective head-to-head comparisons make it a challenge to choose a second-line treatment in the clinic. Areas covered: In this review/meta-opinion, we describe the safety profile of the lenvatinib plus everolimus combination in renal cell carcinoma. The combination of lenvatinib plus everolimus has achieved the highest rates of objective responses and the longest progression free and overall survival in cross-comparison trials. At the same time, the safety profile of this combination, including the rate of total and severe adverse events, the percentage of dose reductions required, and the rate of treatment discontinuation, was less favorable compared with available monotherapy options, suggesting that better management could help to maximize the activity of this combination while protecting patients from undue harm. Expert opinion: Herein, we aim to postulate multidisciplinary recommendations on the advice to offer to patients and caregivers before starting treatment and how to manage the combination from the perspective of daily clinical practice..
Wolchok, J.D.
Rollin, L.
Larkin, J.
(2017). Nivolumab and Ipilimumab in Advanced Melanoma. The new england journal of medicine,
Vol.377
(25),
pp. 2503-2504.
de la Cruz-Merino, L.
Di Guardo, L.
Grob, J.-.
Venosa, A.
Larkin, J.
McArthur, G.A.
Ribas, A.
Ascierto, P.A.
Evans, J.T.
Gomez-Escobar, A.
Barteselli, G.
Eng, S.
Hsu, J.J.
Uyei, A.
Dréno, B.
(2017). Clinical features of serous retinopathy observed with cobimetinib in patients with BRAF-mutated melanoma treated in the randomized coBRIM study. Journal of translational medicine,
Vol.15
(1),
pp. 146-?.
show abstract
Background Serous chorioretinopathy has been associated with MEK inhibitors, including cobimetinib. We describe the clinical features of serous retinopathy observed with cobimetinib in patients with BRAF V600 -mutated melanoma treated in the Phase III coBRIM study.Methods In the coBRIM study, 493 patients were treated in two randomly assigned treatment groups: cobimetinib and vemurafenib (n = 247) or vemurafenib (n = 246). All patients underwent prospective ophthalmic examinations at screening, at regular intervals during the study, and whenever ocular symptoms developed. Patients with serous retinopathy were identified in the study database using a group of relevant and synonymous adverse event terms.Results Eighty-six serous retinopathy events were reported in 70 patients (79 events in 63 cobimetinib and vemurafenib-treated patients vs seven events in seven vemurafenib-treated patients). Most patients with serous retinopathy identified by ophthalmic examination had no symptoms or had mild symptoms, among them reduced visual acuity, blurred vision, dyschromatopsia, and photophobia. Serous retinopathy usually occurred early during cobimetinib and vemurafenib treatment; median time to onset was 1.0 month. Most events were managed by observation and continuation of cobimetinib without dose modification and resolved or were resolving by the data cutoff date (19 Sept 2014).Conclusions Cobimetinib treatment was associated with serous retinopathy in patients with BRAF V600 -mutated melanoma. Retinopathy was generally asymptomatic or mild. Periodic ophthalmologic evaluations at regular intervals and at the manifestation of any visual disturbance are recommended to facilitate early detection and resolution of serous retinopathy while patients are taking cobimetinib. Trial Registration Clinicaltrials.gov (NCT01689519). First received: September 18, 2012..
Seifert, H.
Hirata, E.
Gore, M.
Khabra, K.
Messiou, C.
Larkin, J.
Sahai, E.
(2016). Extrinsic factors can mediate resistance to
BRAF
inhibition in central nervous system melanoma metastases. Pigment cell & melanoma research,
Vol.29
(1),
pp. 92-100.
Bridgeman, V.L.
Wan, E.
Foo, S.
Nathan, M.R.
Welti, J.C.
Frentzas, S.
Vermeulen, P.B.
Preece, N.
Springer, C.J.
Powles, T.
Nathan, P.D.
Larkin, J.
Gore, M.
Vasudev, N.S.
Reynolds, A.R.
(2016). Preclinical Evidence That Trametinib Enhances the Response to Antiangiogenic Tyrosine Kinase Inhibitors in Renal Cell Carcinoma. Molecular cancer therapeutics,
Vol.15
(1),
pp. 172-183.
show abstract
Sunitinib and pazopanib are antiangiogenic tyrosine kinase inhibitors (TKI) used to treat metastatic renal cell carcinoma (RCC). However, the ability of these drugs to extend progression-free and overall survival in this patient population is limited by drug resistance. It is possible that treatment outcomes in RCC patients could be improved by rationally combining TKIs with other agents. Here, we address whether inhibition of the Ras-Raf-MEK-ERK1/2 pathway is a rational means to improve the response to TKIs in RCC. Using a xenograft model of RCC, we found that tumors that are resistant to sunitinib have a significantly increased angiogenic response compared with tumors that are sensitive to sunitinib in vivo. We also observed significantly increased levels of phosphorylated ERK1/2 in the vasculature of resistant tumors, when compared with sensitive tumors. These data suggested that the Ras-Raf-MEK-ERK1/2 pathway, an important driver of angiogenesis in endothelial cells, remains active in the vasculature of TKI-resistant tumors. Using an in vitro angiogenesis assay, we identified that the MEK inhibitor (MEKI) trametinib has potent antiangiogenic activity. We then show that, when trametinib is combined with a TKI in vivo, more effective suppression of tumor growth and tumor angiogenesis is achieved than when either drug is utilized alone. In conclusion, we provide preclinical evidence that combining a TKI, such as sunitinib or pazopanib, with a MEKI, such as trametinib, is a rational and efficacious treatment regimen for RCC..
Atkins, M.B.
Larkin, J.
(2016). Immunotherapy Combined or Sequenced With Targeted Therapy in the Treatment of Solid Tumors: Current Perspectives. Jnci: journal of the national cancer institute,
Vol.108
(6).
Spain, L.
Goode, E.
McGovern, Y.
Joshi, K.
Larkin, J.
(2016). The combination of vemurafenib and cobimetinib in advanced melanoma. Expert opinion on orphan drugs,
Vol.4
(11),
pp. 1105-1111 (7).
Ugurel, S.
Röhmel, J.
Ascierto, P.A.
Flaherty, K.T.
Grob, J.J.
Hauschild, A.
Larkin, J.
Long, G.V.
Lorigan, P.
McArthur, G.A.
Ribas, A.
Robert, C.
Schadendorf, D.
Garbe, C.
(2016). Survival of patients with advanced metastatic melanoma: The impact of novel therapies. European journal of cancer,
Vol.53,
pp. 125-134.
Motzer, R.J.
Hutson, T.E.
Ren, M.
Dutcus, C.
Larkin, J.
(2016). Independent assessment of lenvatinib plus everolimus in patients with metastatic renal cell carcinoma. The lancet oncology,
Vol.17
(1),
pp. e4-e5.
Diem, S.
Kasenda, B.
Spain, L.
Martin-Liberal, J.
Marconcini, R.
Gore, M.
Larkin, J.
(2016). Serum lactate dehydrogenase as an early marker for outcome in patients treated with anti-PD-1 therapy in metastatic melanoma. British journal of cancer,
Vol.114
(3),
pp. 256-261.
Spain, L.
Julve, M.
Larkin, J.
(2016). Combination dabrafenib and trametinib in the management of advanced melanoma with BRAFV600 mutations. Expert opinion on pharmacotherapy,
Vol.17
(7),
pp. 1031-1038.
Porta, C.
Tortora, G.
Larkin, J.M.
Hutson, T.E.
(2016). Management of poor-risk metastatic renal cell carcinoma: current approaches, the role of temsirolimus and future directions. Future oncology,
Vol.12
(4),
pp. 533-549.
show abstract
Targeted therapies have substantially improved outcomes in metastatic renal cell carcinoma (mRCC). As expected, poor-risk patients have the worst outcomes. Temsirolimus is currently the only agent licensed for treatment of poor-risk mRCC patients. It is associated with meaningful improvements in survival and quality of life, highlighting the importance of correctly stratifying risk in mRCC patients so they receive optimal treatment. Currently, data for other targeted therapies in poor-risk patients are relatively sparse. Optimizing outcomes in these patients is the subject of ongoing research, including studies of biomarkers and studies to elucidate the role of nephrectomy and neoadjuvant targeted therapy in poor-risk mRCC patients. The impacts of novel combinations including temsirolimus have also been explored to further improve outcomes. .
Spain, L.
Diem, S.
Larkin, J.
(2016). Management of toxicities of immune checkpoint inhibitors. Cancer treatment reviews,
Vol.44,
pp. 51-60.
Spain, L.
Larkin, J.
(2016). Combination immune checkpoint blockade with ipilimumab and nivolumab in the management of advanced melanoma. Expert opinion on biological therapy,
Vol.16
(3),
pp. 389-396.
Thomas, C.L.
Mortimer, P.S.
Larkin, J.M.
Basu, T.N.
Gore, M.E.
Fearfield, L.
(2016). A mitogen-activated protein kinase kinase inhibitor induced compound skin toxicity with oedema in metastatic malignant melanoma. Clinical and experimental dermatology,
Vol.41
(3),
pp. 267-271.
Seifert, H.
Fisher, R.
Martin-Liberal, J.
Edmonds, K.
Hughes, P.
Khabra, K.
Gore, M.
Larkin, J.
(2016). Prognostic markers and tumour growth kinetics in melanoma patients progressing on vemurafenib. Melanoma research,
Vol.26
(2),
pp. 138-144.
show abstract
The BRAF inhibitor vemurafenib is an effective drug in patients with BRAF mutant metastatic melanoma, but resistance occurs after a median of 6 months. The anti-CTLA4-antibody, ipilimumab, is a standard first-line and second-line treatment option in Europe, with a median time to response of 2-3 months, but some patients show rapid clinical deterioration before that. The aim of this analysis was to identify prognostic markers for survival after failure of vemurafenib treatment to identify patients who have a sufficient life expectancy to respond to new immunotherapy treatments. We retrospectively analysed 101 consecutive unselected patients treated with vemurafenib for metastatic melanoma at a single institution. The association between clinical parameters and death within 3 months after cessation of vemurafenib (n=69) was assessed by binary logistic and Cox regression. Of the patients, 45% died within 3 months of progression on vemurafenib. Elevated baseline serum lactate dehydrogenase, absence of normalization of serum lactate dehydrogenase on vemurafenib therapy, performance status of at least 2 at progression and time from primary tumour to metastatic disease less than 5 years were identified as poor prognostic markers. In an exploratory tumour growth kinetics analysis (n=16), we found that following cessation of vemurafenib, approximately a third each showed a stable, decelerated or accelerated rate of tumour growth. Patients with these poor prognostic markers are unlikely to have sufficient life expectancy to complete ipilimumab treatment after failure with vemurafenib. Consideration needs to be given to the elective use of immunotherapy before patients become resistant to vemurafenib. This requires prospective randomized evaluation. Our tumour growth kinetics analysis requires confirmation; however, it may suggest that intermittent vemurafenib treatment should be investigated in clinical trials..
Gravis, G.
Chanez, B.
Derosa, L.
Beuselinck, B.
Barthelemy, P.
Laguerre, B.
Brachet, P.-.
Joly, F.
Escudier, B.
Harrison, D.J.
Laird, A.
Vasudev, N.
Ralph, C.
Larkin, J.
Lote, H.
Salem, N.
Walz, J.
Thomassin, J.
Sfumato, P.
Stewart, G.D.
Boher, J.M.
Renal Cross Channel Group,
(2016). Effect of glandular metastases on overall survival of patients with metastatic clear cell renal cell carcinoma in the antiangiogenic therapy era. Urologic oncology,
Vol.34
(4),
pp. 167.e17-167.e23.
show abstract
Background Glandular metastases (GMs) (pancreas, breast, parotid, thyroid, or contralateral adrenal) are rare in metastatic clear cell renal cell carcinoma (mccRCC). In a multicenter study we have assessed outcome from mccRCC with or without GMs.Patients and methods Patients with mccRCC and GM or non-GM (NGM) at first presentation of mccRCC, treated at 9 European centers (5 French, 3 UK, and 1 Belgian centers) between January 2004 and October 2013, were retrospectively analyzed. Association between overall survival (OS) and site of metastases was assessed using the log-rank test for univariate analysis and the chi-square test for multivariable Cox regression.Results In all, 138 patients with GM mccRCC and 420 with NGM mccRCC were included; 37.2% patients with GM had Memorial Sloan-Kettering Cancer Center (MSKCC)-favorable risk vs. 18% NGM patients; 10.7% patients with GM had MSKCC-poor risk vs. 27% NGM patients (P<0.0001). Median interval from metastases to treatment was 4.2 months (range: 0-221.3mo). Median OS was 61.5 months (51.4-81.6mo) for GM and 37.4 months (31.3-42mo) for NGM (hazard ratio [HR] = 1.7; 95% CI = 1.3-2.2, P<0.001). In univariate OS analysis, age, delay between initial diagnosis and metastases, MSKCC, bone/lung metastases, and GM or NGM group were significant parameters (P<0.001). In multivariate analysis, adjusted according to MSKCC risk group, NGM vs. GM was a strong prognostic factor (HR = 1.4; 95% CI = 1.0-1.8, P=0.026); bone or liver metastases were also significant (HR = 1.3; 95% CI = 1.1-1.7, P<0.02; HR = 1.4; 95% CI = 1.1-1.7, P<0.02, respectively). Even in patients without bone or liver metastases, GM status was significant (HR = 1.8; 95% CI = 1.2-2.7, P<0.004).Conclusions This large retrospective study shows that the presence of at least 1 GM site in development of mccRCC was associated with a significantly longer OS. The presence of GMs vs. NGM disease was an independent prognostic factor for survival irrespective of the presence or absence of bone or liver metastases. This finding could affect daily practice in which patients with mccRCC and GMs should receive more aggressive treatment with a potential for long-term survival. The causal mechanisms for this improved prognosis in GM mccRCC would be evaluated in translational studies..
Bowyer, S.
Prithviraj, P.
Lorigan, P.
Larkin, J.
McArthur, G.
Atkinson, V.
Millward, M.
Khou, M.
Diem, S.
Ramanujam, S.
Kong, B.
Liniker, E.
Guminski, A.
Parente, P.
Andrews, M.C.
Parakh, S.
Cebon, J.
Long, G.V.
Carlino, M.S.
Klein, O.
(2016). Efficacy and toxicity of treatment with the anti-CTLA-4 antibody ipilimumab in patients with metastatic melanoma after prior anti-PD-1 therapy. British journal of cancer,
Vol.114
(10),
pp. 1084-1089.
show abstract
Background Recent phase III clinical trials have established the superiority of the anti-PD-1 antibodies pembrolizumab and nivolumab over the anti-CTLA-4 antibody ipilimumab in the first-line treatment of patients with advanced melanoma. Ipilimumab will be considered for second-line treatment after the failure of anti-PD-1 therapy.Methods We retrospectively identified a cohort of 40 patients with metastatic melanoma who received single-agent anti-PD-1 therapy with pembrolizumab or nivolumab and were treated on progression with ipilimumab at a dose of 3 mg kg(-1) for a maximum of four doses.Results Ten percent of patients achieved an objective response to ipilimumab, and an additional 8% experienced prolonged (>6 months) stable disease. Thirty-five percent of patients developed grade 3-5 immune-related toxicity associated with ipilimumab therapy. The most common high-grade immune-related toxicity was diarrhoea. Three patients (7%) developed grade 3-5 pneumonitis leading to death in one patient.Conclusions Ipilimumab therapy can induce responses in patients who fail the anti-PD-1 therapy with response rates comparable to previous reports. There appears to be an increased frequency of high-grade immune-related adverse events including pneumonitis that warrants close surveillance..
Powles, T.
Brown, J.
Larkin, J.
Jones, R.
Ralph, C.
Hawkins, R.
Chowdhury, S.
Boleti, E.
Bhal, A.
Fife, K.
Webb, A.
Crabb, S.
Geldart, T.
Hill, R.
Dunlop, J.
Hall, P.E.
McLaren, D.
Ackerman, C.
Beltran, L.
Nathan, P.
(2016). A randomized, double-blind phase II study evaluating cediranib versus cediranib and saracatinib in patients with relapsed metastatic clear-cell renal cancer (COSAK). Annals of oncology,
Vol.27
(5),
pp. 880-886.
Spain, L.
Higgins, R.
Gopalakrishnan, K.
Turajlic, S.
Gore, M.
Larkin, J.
(2016). Acute renal allograft rejection after immune checkpoint inhibitor therapy for metastatic melanoma. Annals of oncology,
Vol.27
(6),
pp. 1135-1137.
Spain, L.
Larkin, J.
Martin-Liberal, J.
(2016). Determining predictive factors for immune checkpoint inhibitor toxicity: Response to Letter to the Editors "A case report of insulin-dependent diabetes as immune-related toxicity of pembrolizumab: presentation, management and outcome". Cancer immunology, immunotherapy : cii,
Vol.65
(6),
pp. 769-770.
Spain, L.
Larkin, J.
(2016). Weighing up the pros and cons of immune checkpoint inhibitors in the treatment of melanoma. Immunotherapy,
Vol.8
(6),
pp. 677-679.
Rini, B.I.
Dorff, T.B.
Elson, P.
Rodriguez, C.S.
Shepard, D.
Wood, L.
Humbert, J.
Pyle, L.
Wong, Y.-.
Finke, J.H.
Rayman, P.A.
Larkin, J.M.
Garcia, J.A.
Plimack, E.R.
(2016). Active surveillance in metastatic renal-cell carcinoma: a prospective, phase 2 trial. The lancet. oncology,
Vol.17
(9),
pp. 1317-1324.
show abstract
Background A subset of patients with metastatic renal-cell carcinoma show indolent growth of metastases. Because of the toxicity and non-curative nature of systemic therapy, some of these patients could benefit from initial active surveillance. We aimed to characterise the time to initiation of systemic therapy in patients with metastatic renal-cell carcinoma under active surveillance.Methods In this prospective phase 2 trial, we enrolled patients with treatment-naive, asymptomatic, metastatic renal-cell carcinoma from five hospitals in the USA, Spain, and the UK. Patients were radiographically assessed at baseline, every 3 months for year 1, every 4 months for year 2, then every 6 months thereafter. Patients continued on observation until initiation of systemic therapy for metastatic renal-cell carcinoma; a decision that was made at the discretion of the treating physician and patient. The primary endpoint of the study was time to initiation of systemic therapy in the per-protocol population. The follow-up of patients is ongoing.Findings Between Aug 21, 2008, and June 7, 2013, we enrolled 52 patients. Median follow-up of patients in the study was 38·1 months (IQR 29·4-48·9). In the 48 patients included in analysis, median time on surveillance from registration on study until initiation of systemic therapy was 14·9 months (95% CI 10·6-25·0). Multivariate analysis showed that higher numbers of International Metastatic Database Consortium (IMDC) adverse risk factors (p=0·0403) and higher numbers of metastatic disease sites (p=0·0414) were associated with a shorter surveillance period. 22 (46%) patients died during the study period, all from metastatic renal-cell carcinoma.Interpretation A subset of patients with metastatic renal-cell carcinoma can safely undergo surveillance before starting systemic therapy. Additional investigation is required to further define the benefits and risks of this approach.Funding None..
Ascierto, P.A.
McArthur, G.A.
Dréno, B.
Atkinson, V.
Liszkay, G.
Di Giacomo, A.M.
Mandalà, M.
Demidov, L.
Stroyakovskiy, D.
Thomas, L.
de la Cruz-Merino, L.
Dutriaux, C.
Garbe, C.
Yan, Y.
Wongchenko, M.
Chang, I.
Hsu, J.J.
Koralek, D.O.
Rooney, I.
Ribas, A.
Larkin, J.
(2016). Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. The lancet. oncology,
Vol.17
(9),
pp. 1248-1260.
show abstract
Background The combination of cobimetinib with vemurafenib improves progression-free survival compared with placebo and vemurafenib in previously untreated patients with BRAF(V600)-mutant advanced melanoma, as previously reported in the coBRIM study. In this Article, we report updated efficacy results, including overall survival and safety after longer follow-up, and selected biomarker correlative studies.Methods In this double-blind, randomised, placebo-controlled, multicentre study, adult patients (aged ≥18 years) with histologically confirmed BRAF(V600) mutation-positive unresectable stage IIIC or stage IV melanoma were randomly assigned (1:1) using an interactive response system to receive cobimetinib (60 mg once daily for 21 days followed by a 7-day rest period in each 28-day cycle) or placebo, in combination with oral vemurafenib (960 mg twice daily). Progression-free and overall survival were primary and secondary endpoints, respectively; all analyses were done on the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01689519, and is ongoing but no longer recruiting participants.Findings Between Jan 8, 2013, and Jan 31, 2014, 495 eligible adult patients were enrolled and randomly assigned to the cobimetinib plus vemurafenib group (n=247) or placebo plus vemurafenib group (n=248). At a median follow-up of 14·2 months (IQR 8·5-17·3), the updated investigator-assessed median progression-free survival was 12·3 months (95% CI 9·5-13·4) for cobimetinib and vemurafenib versus 7·2 months (5·6-7·5) for placebo and vemurafenib (HR 0·58 [95% CI 0·46-0·72], p<0·0001). The final analysis for overall survival occurred when 255 (52%) patients had died (Aug 28, 2015). Median overall survival was 22·3 months (95% CI 20·3-not estimable) for cobimetinib and vemurafenib versus 17·4 months (95% CI 15·0-19·8) for placebo and vemurafenib (HR 0·70, 95% CI 0·55-0·90; p=0·005). The safety profile for cobimetinib and vemurafenib was tolerable and manageable, and no new safety signals were observed with longer follow-up. The most common grade 3-4 adverse events occurring at a higher frequency in patients in the cobimetinib and vemurafenib group compared with the vemurafenib group were γ-glutamyl transferase increase (36 [15%] in the cobimetinib and vemurafenib group vs 25 [10%] in the placebo and vemurafenib group), blood creatine phosphokinase increase (30 [12%] vs one [<1%]), and alanine transaminase increase (28 [11%] vs 15 [6%]). Serious adverse events occurred in 92 patients (37%) in the cobimetinib and vemurafenib group and 69 patients (28%) in the vemurafenib group. Pyrexia (six patients [2%]) and dehydration (five patients [2%]) were the most common serious adverse events reported in the cobimetinib and vemurafenib group. A total of 259 patients have died: 117 (47%) in the cobimetinib and vemurafenib group and 142 (58%) in the vemurafenib group. The primary cause of death was disease progression in most patients: 109 (93%) of 117 in the cobimetinib and vemurafenib group and 133 (94%) of 142 in the vemurafenib group.Interpretation These data confirm the clinical benefit of cobimetinib combined with vemurafenib and support the use of the combination as a standard first-line approach to improve survival in patients with advanced BRAF(V600)-mutant melanoma.Funding F Hoffmann-La Roche-Genentech..
Turajlic, S.
Larkin, J.
(2016). Systemic treatment of advanced papillary renal cell carcinoma: Where next?. European journal of cancer (oxford, england : 1990),
Vol.69,
pp. 223-225.
Larkin, J.
Lao, C.D.
Urba, W.J.
McDermott, D.F.
Horak, C.
Jiang, J.
Wolchok, J.D.
(2015). Efficacy and Safety of Nivolumab in Patients With BRAF V600 Mutant and BRAF Wild-Type Advanced Melanoma. Jama oncology,
Vol.1
(4),
pp. 433-433.
Rothermundt, C.
Bailey, A.
Cerbone, L.
Eisen, T.
Escudier, B.
Gillessen, S.
Grünwald, V.
Larkin, J.
McDermott, D.
Oldenburg, J.
Porta, C.
Rini, B.
Schmidinger, M.
Sternberg, C.
Putora, P.M.
(2015). Algorithms in the First-Line Treatment of Metastatic Clear Cell Renal Cell Carcinoma—Analysis Using Diagnostic Nodes. The oncologist,
Vol.20
(9),
pp. 1028-1035.
show abstract
Abstract
Background.
With the advent of targeted therapies, many treatment options in the first-line setting of metastatic clear cell renal cell carcinoma (mccRCC) have emerged. Guidelines and randomized trial reports usually do not elucidate the decision criteria for the different treatment options. In order to extract the decision criteria for the optimal therapy for patients, we performed an analysis of treatment algorithms from experts in the field.
Materials and Methods.
Treatment algorithms for the treatment of mccRCC from experts of 11 institutions were obtained, and decision trees were deduced. Treatment options were identified and a list of unified decision criteria determined. The final decision trees were analyzed with a methodology based on diagnostic nodes, which allows for an automated cross-comparison of decision trees. The most common treatment recommendations were determined, and areas of discordance were identified.
Results.
The analysis revealed heterogeneity in most clinical scenarios. The recommendations selected for first-line treatment of mccRCC included sunitinib, pazopanib, temsirolimus, interferon-α combined with bevacizumab, high-dose interleukin-2, sorafenib, axitinib, everolimus, and best supportive care. The criteria relevant for treatment decisions were performance status, Memorial Sloan Kettering Cancer Center risk group, only or mainly lung metastases, cardiac insufficiency, hepatic insufficiency, age, and “zugzwang” (composite of multiple, related criteria).
Conclusion.
In the present study, we used diagnostic nodes to compare treatment algorithms in the first-line treatment of mccRCC. The results illustrate the heterogeneity of the decision criteria and treatment strategies for mccRCC and how available data are interpreted and implemented differently among experts.
Implications for Practice:
The data provided in the present report should not be considered to serve as treatment recommendations for the management of treatment-naïve patients with multiple metastases from metastatic clear cell renal cell carcinoma outside a clinical trial; however, the data highlight the different treatment options and the criteria used to select them. The diversity in decision making and how results from phase III trials can be interpreted and implemented differently in daily practice are demonstrated.
.
Lorigan, P.
Ascierto, P.A.
Dummer, R.
Eggermont, A.M.
Flaherty, K.T.
Garbe, C.
Gogas, H.
Hauschild, A.
Kefford, R.F.
Kirkwood, J.M.
Larkin, J.
Long, G.V.
Maio, M.
McArthur, G.A.
Ribas, A.
Robert, C.
Schadendorf, D.
Sondak, V.K.
Wolchok, J.D.
Hudson, A.M.
(2015). Expanded access programmes: patient interests versus clinical trial integrity. Lancet oncology,
Vol.16
(1),
pp. 15-17.
Coupe, N.
Corrie, P.
Hategan, M.
Larkin, J.
Gore, M.
Gupta, A.
Wise, A.
Suter, S.
Ciria, C.
Love, S.
Collins, L.
Middleton, M.R.
(2015). PACMEL: a phase 1 dose escalation trial of trametinib (GSK1120212) in combination with paclitaxel. Eur j cancer,
Vol.51
(3),
pp. 359-366.
show abstract
BACKGROUND: We sought to determine the maximal tolerated dose of the MEK inhibitor trametinib with weekly paclitaxel, with a view to exploring the combination's activity in melanoma lacking a BRAF V600 mutation. METHODS: In this phase 1 study we used a fixed dose of paclitaxel (80 mg/m2 intravenous (IV) on days 1, 8 and 15 of each 4 week cycle) and escalated the dose of trametinib (to a maximum 2mg orally (PO) daily), following a 3+3 design. Eligible patients had advanced melanoma and could have received up to two previous lines of treatment for metastatic disease. FINDINGS: 15 patients were enrolled, all but one of whose melanoma was wild type for BRAF at codon 600. The maximal monotherapy dose of trametinib proved tolerable with weekly paclitaxel. The most frequent adverse events observed were rash and fatigue. Six (40%) partial responses were reported, including four of eight patients with NRAS mutations. Median progression free survival was 5.5 months (95% confidence interval (CI) 1.8-7.8 months) and overall survival, 14.1 months (95% CI 4.6-not reached). INTERPRETATION: Trametinib can safely be given with weekly paclitaxel at the full monotherapy dose. In this small group promising progression free and overall survival were observed in patients with melanoma lacking a V600 BRAF mutation..
Larkin, J.
Paine, A.
Foley, G.
Mitchell, S.
Chen, C.
(2015). First-line treatment in the management of advanced renal cell carcinoma: systematic review and network meta-analysis. Expert opinion on pharmacotherapy,
Vol.16
(13),
pp. 1915-1927.
Larkin, J.
Chiarion-Sileni, V.
Gonzalez, R.
Grob, J.J.
Cowey, C.L.
Lao, C.D.
Schadendorf, D.
Dummer, R.
Smylie, M.
Rutkowski, P.
Ferrucci, P.F.
Hill, A.
Wagstaff, J.
Carlino, M.S.
Haanen, J.B.
Maio, M.
Marquez-Rodas, I.
McArthur, G.A.
Ascierto, P.A.
Long, G.V.
Callahan, M.K.
Postow, M.A.
Grossmann, K.
Sznol, M.
Dreno, B.
Bastholt, L.
Yang, A.
Rollin, L.M.
Horak, C.
Hodi, F.S.
Wolchok, J.D.
(2015). Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. New england journal of medicine,
Vol.373
(1),
pp. 23-34.
Martin-Liberal, J.
Kordbacheh, T.
Larkin, J.
(2015). Safety of pembrolizumab for the treatment of melanoma. Expert opinion on drug safety,
Vol.14
(6),
pp. 957-964.
Sinha, R.
Larkin, J.
Fearfield, L.
(2015). Clinical resolution of vemurafenib-induced squamous cell carcinoma with topical 5-fluorouracil. British journal of dermatology,
Vol.172
(4),
pp. 1135-1136.
Hirata, E.
Girotti, M.R.
Viros, A.
Hooper, S.
Spencer-Dene, B.
Matsuda, M.
Larkin, J.
Marais, R.
Sahai, E.
(2015). Intravital Imaging Reveals How BRAF Inhibition Generates Drug-Tolerant Microenvironments with High Integrin β1/FAK Signaling. Cancer cell,
Vol.27
(4),
pp. 574-588.
Weber, J.S.
D'Angelo, S.P.
Minor, D.
Hodi, F.S.
Gutzmer, R.
Neyns, B.
Hoeller, C.
Khushalani, N.I.
Miller, W.H.
Lao, C.D.
Linette, G.P.
Thomas, L.
Lorigan, P.
Grossmann, K.F.
Hassel, J.C.
Maio, M.
Sznol, M.
Ascierto, P.A.
Mohr, P.
Chmielowski, B.
Bryce, A.
Svane, I.M.
Grob, J.-.
Krackhardt, A.M.
Horak, C.
Lambert, A.
Yang, A.S.
Larkin, J.
(2015). Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. The lancet oncology,
Vol.16
(4),
pp. 375-384.
Kovac, M.
Navas, C.
Horswell, S.
Salm, M.
Bardella, C.
Rowan, A.
Stares, M.
Castro-Giner, F.
Fisher, R.
de Bruin, E.C.
Kovacova, M.
Gorman, M.
Makino, S.
Williams, J.
Jaeger, E.
Jones, A.
Howarth, K.
Larkin, J.
Pickering, L.
Gore, M.
Nicol, D.L.
Hazell, S.
Stamp, G.
O’Brien, T.
Challacombe, B.
Matthews, N.
Phillimore, B.
Begum, S.
Rabinowitz, A.
Varela, I.
Chandra, A.
Horsfield, C.
Polson, A.
Tran, M.
Bhatt, R.
Terracciano, L.
Eppenberger-Castori, S.
Protheroe, A.
Maher, E.
El Bahrawy, M.
Fleming, S.
Ratcliffe, P.
Heinimann, K.
Swanton, C.
Tomlinson, I.
(2015). Recurrent chromosomal gains and heterogeneous driver mutations characterise papillary renal cancer evolution. Nature communications,
Vol.6
(1).
Thomas, C.L.
Mortimer, P.S.
Larkin, J.M.
Basu, T.N.
Gore, M.E.
Fearfield, L.
(2015). MEK-inhibitor induced compound skin toxicity with oedema in metastatic malignant melanoma: a case series. Australasian journal of dermatology,
Vol.56,
pp. 78-78.
Bex, A.
Larkin, J.
Voss, M.
(2015). Challenging the Treatment Paradigm for Advanced Renal Cell Carcinoma: A Review of Systemic and Localized Therapies. American society of clinical oncology educational book,
(35),
pp. e239-e247.
show abstract
The current standard of care for the management of advanced renal cell carcinoma (RCC) revolves around systemic therapy with molecularly targeted agents. Over the last decade, a total of seven targeted drugs have been approved but, altogether, only exploit two molecular targets in this disease: the vascular endothelial growth factor (VEGF) axis and the mammalian target of rapamycin (mTOR). Introduction of these agents has markedly improved outcomes compared with those in the cytokine era, yet comparatively little progress has been made since registration of the first targeted therapeutics occurred 10 years ago. In this article, we review efforts to improve on this current treatment paradigm. We discuss novel targets in this disease and corresponding new agents under investigation. The article dedicates particular attention to targeted immunotherapeutics, which are rapidly emerging as a new category of interest in this disease. Last, we review current data supporting the use of surgical interventions to improve outcomes in patients with metastatic disease. .
Motzer, R.J.
Escudier, B.
McDermott, D.F.
George, S.
Hammers, H.J.
Srinivas, S.
Tykodi, S.S.
Sosman, J.A.
Procopio, G.
Plimack, E.R.
Castellano, D.
Choueiri, T.K.
Gurney, H.
Donskov, F.
Bono, P.
Wagstaff, J.
Gauler, T.C.
Ueda, T.
Tomita, Y.
Schutz, F.A.
Kollmannsberger, C.
Larkin, J.
Ravaud, A.
Simon, J.S.
Xu, L.-.
Waxman, I.M.
Sharma, P.
(2015). Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. New england journal of medicine,
Vol.373
(19),
pp. 1803-1813.
Schadendorf, D.
Amonkar, M.M.
Stroyakovskiy, D.
Levchenko, E.
Gogas, H.
de Braud, F.
Grob, J.-.
Bondarenko, I.
Garbe, C.
Lebbe, C.
Larkin, J.
Chiarion-Sileni, V.
Millward, M.
Arance, A.
Mandalà, M.
Flaherty, K.T.
Nathan, P.
Ribas, A.
Robert, C.
Casey, M.
DeMarini, D.J.
Irani, J.G.
Aktan, G.
Long, G.V.
(2015). Health-related quality of life impact in a randomised phase III study of the combination of dabrafenib and trametinib versus dabrafenib monotherapy in patients with BRAF V600 metastatic melanoma. European journal of cancer,
Vol.51
(7),
pp. 833-840.
Yousaf, N.
Davidson, M.
Goode, E.
Thomas, C.
Hung, R.
Gore, M.
Larkin, J.
(2015). The cost of ipilimumab toxicity. Melanoma research,
Vol.25
(3),
pp. 259-264.
Pickering, L.M.
Larkin, J.
(2015). Carbonic anhydrase IX in resected clear cell RCC. Nature reviews urology,
Vol.12
(6),
pp. 309-310.
Martin-Liberal, J.
Furness, A.J.
Joshi, K.
Peggs, K.S.
Quezada, S.A.
Larkin, J.
(2015). Anti-programmed cell death-1 therapy and insulin-dependent diabetes: a case report. Cancer immunology, immunotherapy,
Vol.64
(6),
pp. 765-767.
Gulati, S.
Turajlic, S.
Larkin, J.
Bates, P.A.
Swanton, C.
(2015). Relapse models for clear cell renal carcinoma. The lancet oncology,
Vol.16
(8),
pp. e376-e378.
Long, G.V.
Stroyakovskiy, D.
Gogas, H.
Levchenko, E.
de Braud, F.
Larkin, J.
Garbe, C.
Jouary, T.
Hauschild, A.
Grob, J.-.
Chiarion-Sileni, V.
Lebbe, C.
Mandalà, M.
Millward, M.
Arance, A.
Bondarenko, I.
Haanen, J.B.
Hansson, J.
Utikal, J.
Ferraresi, V.
Kovalenko, N.
Mohr, P.
Probachai, V.
Schadendorf, D.
Nathan, P.
Robert, C.
Ribas, A.
DeMarini, D.J.
Irani, J.G.
Swann, S.
Legos, J.J.
Jin, F.
Mookerjee, B.
Flaherty, K.
(2015). Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. The lancet,
Vol.386
(9992),
pp. 444-451.
Wolchok, J.D.
Chiarion-Sileni, V.
Gonzalez, R.
Rutkowski, P.
Grob, J.J.
Cowey, C.L.
Lao, C.D.
Schadendorf, D.
Ferrucci, P.F.
Smylie, M.
Dummer, R.
Hill, A.
Haanen, J.
Maio, M.
McArthur, G.
Yang, A.
Rollin, L.
Horak, C.
Larkin, J.
Hodi, F.S.
(2015). CHECKMATE 067: A PHASE III RANDOMIZED DOUBLE-BLIND STUDY OF NIVOLUMAB (NIVO) MONOTHERAPY OR NIVO COMBINED WITH IPILIMUMAB (IPI) VERSUS IPI MONOTHERAPY IN PREVIOUSLY UNTREATED PATIENTS (PTS) WITH ADVANCED MELANOMA (MEL). Asia-pacific journal of clinical oncology,
Vol.11,
pp. 68-68.
Soultati, A.
Stares, M.
Swanton, C.
Larkin, J.
Turajlic, S.
(2015). How should clinicians address intratumour heterogeneity in clear cell renal cell carcinoma?. Current opinion in urology,
Vol.25
(5),
pp. 358-366.
Moriceau, G.
Hugo, W.
Hong, A.
Shi, H.
Kong, X.
Yu, C.C.
Koya, R.C.
Samatar, A.A.
Khanlou, N.
Braun, J.
Ruchalski, K.
Seifert, H.
Larkin, J.
Dahlman, K.B.
Johnson, D.B.
Algazi, A.
Sosman, J.A.
Ribas, A.
Lo, R.S.
(2015). Tunable-combinatorial mechanisms of acquired resistance limit the efficacy of BRAF/MEK cotargeting but result in melanoma drug addiction. Cancer cell,
Vol.27
(2),
pp. 240-256.
show abstract
Combined BRAF- and MEK-targeted therapy improves upon BRAF inhibitor (BRAFi) therapy but is still beset by acquired resistance. We show that melanomas acquire resistance to combined BRAF and MEK inhibition by augmenting or combining mechanisms of single-agent BRAFi resistance. These double-drug resistance-associated genetic configurations significantly altered molecular interactions underlying MAPK pathway reactivation. (V600E)BRAF, expressed at supraphysiological levels because of (V600E)BRAF ultra-amplification, dimerized with and activated CRAF. In addition, MEK mutants enhanced interaction with overexpressed (V600E)BRAF via a regulatory interface at R662 of (V600E)BRAF. Importantly, melanoma cell lines selected for resistance to BRAFi+MEKi, but not those to BRAFi alone, displayed robust drug addiction, providing a potentially exploitable therapeutic opportunity..
Sinha, R.
Larkin, J.
Gore, M.
Fearfield, L.
(2015). Cutaneous toxicities associated with vemurafenib therapy in 107 patients withBRAFV600E mutation-positive metastatic melanoma, including recognition and management of rare presentations. British journal of dermatology,
Vol.173
(4),
pp. 1024-1031.
Turajlic, S.
Larkin, J.
Swanton, C.
(2015). Academically led clinical trials: challenges and opportunities. Annals of oncology,
Vol.26
(10),
pp. 2010-2011.
Motzer, R.
Hutson, T.
Glen, H.
Michaelson, M.D.
Molina, A.
Eisen, T.
Jassem, J.
Zolnierek, J.
Maroto, P.
Mellado, B.
Melichar, B.
Tomasek, J.
Kim, H.-.
Wood, K.
Dutcus, C.
Larkin, J.
(2015). Randomized phase 2 three-arm trial of lenvatinib (LEN), everolimus (EVE), and LEN plus EVE in patients (pts) with metastatic renal cell carcinoma (mRCC). Oncology research and treatment,
Vol.38,
pp. 203-204.
Ahmad, S.S.
Qian, W.
Ellis, S.
Mason, E.
Khattak, M.A.
Gupta, A.
Shaw, H.
Quinton, A.
Kovarikova, J.
Thillai, K.
Rao, A.
Board, R.
Nobes, J.
Dalgleish, A.
Grumett, S.
Maraveyas, A.
Danson, S.
Talbot, T.
Harries, M.
Marples, M.
Plummer, R.
Kumar, S.
Nathan, P.
Middleton, M.R.
Larkin, J.
Lorigan, P.
Wheater, M.
Ottensmeier, C.H.
Corrie, P.G.
(2015). Ipilimumab in the real world. Melanoma research,
Vol.25
(5),
pp. 432-442.
Kanu, N.
Grönroos, E.
Martinez, P.
Burrell, R.A.
Yi Goh, X.
Bartkova, J.
Maya-Mendoza, A.
Mistrík, M.
Rowan, A.J.
Patel, H.
Rabinowitz, A.
East, P.
Wilson, G.
Santos, C.R.
McGranahan, N.
Gulati, S.
Gerlinger, M.
Birkbak, N.J.
Joshi, T.
Alexandrov, L.B.
Stratton, M.R.
Powles, T.
Matthews, N.
Bates, P.A.
Stewart, A.
Szallasi, Z.
Larkin, J.
Bartek, J.
Swanton, C.
(2015). SETD2 loss-of-function promotes renal cancer branched evolution through replication stress and impaired DNA repair. Oncogene,
Vol.34
(46),
pp. 5699-5708.
Wilkins, A.
Furness, A.
Corbett, R.W.
Bloomfield, A.
Porta, N.
Morris, S.
Ali, Z.
Larkin, J.
Harrington, K.
(2015). The melanoma-specific graded prognostic assessment does not adequately discriminate prognosis in a modern population with brain metastases from malignant melanoma. British journal of cancer,
Vol.113
(9),
pp. 1275-1281.
show abstract
The melanoma-specific graded prognostic assessment (msGPA) assigns patients with brain metastases from malignant melanoma to 1 of 4 prognostic groups. It was largely derived using clinical data from patients treated in the era that preceded the development of newer therapies such as BRAF, MEK and immune checkpoint inhibitors. Therefore, its current relevance to patients diagnosed with brain metastases from malignant melanoma is unclear. This study is an external validation of the msGPA in two temporally distinct British populations.Performance of the msGPA was assessed in Cohort I (1997-2008, n=231) and Cohort II (2008-2013, n=162) using Kaplan-Meier methods and Harrell's c-index of concordance. Cox regression was used to explore additional factors that may have prognostic relevance.The msGPA does not perform well as a prognostic score outside of the derivation cohort, with suboptimal statistical calibration and discrimination, particularly in those patients with an intermediate prognosis. Extra-cerebral metastases, leptomeningeal disease, age and potential use of novel targeted agents after brain metastases are diagnosed, should be incorporated into future prognostic models.An improved prognostic score is required to underpin high-quality randomised controlled trials in an area with a wide disparity in clinical care..
Motzer, R.J.
Hutson, T.E.
Glen, H.
Michaelson, M.D.
Molina, A.
Eisen, T.
Jassem, J.
Zolnierek, J.
Maroto, J.P.
Mellado, B.
Melichar, B.
Tomasek, J.
Kremer, A.
Kim, H.-.
Wood, K.
Dutcus, C.
Larkin, J.
(2015). Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. The lancet oncology,
Vol.16
(15),
pp. 1473-1482.
Larkin, J.
Chiarion-Sileni, V.
Gonzalez, R.
Grob, J.-.
Cowey, C.L.
Lao, C.D.
Wagstaff, J.
Hogg, D.
Hill, A.
Carlino, M.S.
Wolter, P.
Lebbe, C.
Schachter, J.
Thomas, L.
Hassal, J.C.
Lorigan, P.
Walker, D.
Jiang, J.
Hodi, F.S.
Wolchok, J.D.
(2015). EFFICACY AND SAFETY IN KEY PATIENT SUBGROUPS OF NIVOLUMAB (NIVO) ALONE OR COMBINED WITH IPILIMUMAB (IPI) VERSUS IPI ALONE IN TREATMENT-NAIVE PATIENTS WITH ADVANCED MELANOMA (MEL) (CHECKMATE 067). Asia-pacific journal of clinical oncology,
Vol.11,
pp. 126-126.
Spain, L.
Younger, E.
Hatipoglu, E.
Larkin, J.
(2015). Pembrolizumab in the management of metastatic melanoma. Melanoma management,
Vol.2
(4),
pp. 315-325.
show abstract
Pembrolizumab is a humanized IgG4 anti-PD-1 antibody that plays a major role in the treatment of advanced melanoma. Through blockade of PD-1, it leads to an increase in effector T-cell activity in the tumor microenvironment. Clinical trial outcomes for pembrolizumab in addition to pharmacokinetics, pharmacodynamics and safety of the compound are discussed in this article. Phase I trials have demonstrated safety and efficacy of pembrolizumab in advanced, pretreated melanoma patients. When compared with chemotherapy in a Phase II trial of ipilimumab-refractory patients, those treated with pembrolizumab showed superior progression-free survival. In addition, in the pivotal Phase III trial pembrolizumab improved overall survival compared with ipilimumab in patients naive to immune checkpoint inhibition. Pembrolizumab is well tolerated and has a favorable safety profile. Common adverse events are fatigue, rash, itching and diarrhea. Less frequent immune-related adverse events include hypothyroidism, colitis, hepatitis and pneumonitis. .
Diem, S.
Kasenda, B.
Martin-Liberal, J.
Lee, A.
Chauhan, D.
Gore, M.
Larkin, J.
(2015). Prognostic score for patients with advanced melanoma treated with ipilimumab. European journal of cancer,
Vol.51
(18),
pp. 2785-2791.
Turajlic, S.
Larkin, J.
Swanton, C.
(2015). SnapShot: Renal Cell Carcinoma. Cell,
Vol.163
(6),
pp. 1556-1556.e1.
Gore, M.
Larkin, J.
(2015). Precision oncology: where next?. The lancet oncology,
Vol.16
(16),
pp. 1593-1595.
Dummer, R.
Schadendorf, D.
Ascierto, P.A.
Larkin, J.
Lebbé, C.
Hauschild, A.
(2015). Integrating first-line treatment options into clinical practice. Melanoma research,
Vol.25
(6),
pp. 461-469.
Richman, J.
Martin-Liberal, J.
Diem, S.
Larkin, J.
(2015). BRAF and MEK inhibition for the treatment of advanced BRAF mutant melanoma. Expert opinion on pharmacotherapy,
Vol.16
(9),
pp. 1285-1297.
Jamal-Hanjani, M.
Quezada, S.A.
Larkin, J.
Swanton, C.
(2015). Translational Implications of Tumor Heterogeneity. Clinical cancer research,
Vol.21
(6),
pp. 1258-1266.
show abstract
Abstract
Advances in next-generation sequencing and bioinformatics have led to an unprecedented view of the cancer genome and its evolution. Genomic studies have demonstrated the complex and heterogeneous clonal landscape of tumors of different origins and the potential impact of intratumor heterogeneity on treatment response and resistance, cancer progression, and the risk of disease relapse. However, the significance of subclonal mutations, in particular mutations in driver genes, and their evolution through time and their dynamics in response to cancer therapies, is yet to be determined. The necessary tools are now available to prospectively determine whether clonal heterogeneity can be used as a biomarker of clinical outcome and to what extent subclonal somatic alterations might influence clinical outcome. Studies that use longitudinal tissue sampling, integrating both genomic and clinical data, have the potential to reveal the subclonal composition and track the evolution of tumors to address these questions and to begin to define the breadth of genetic diversity in different tumor types and its relevance to patient outcome. Such studies may provide further evidence for drug-resistance mechanisms informing combinatorial, adaptive, and tumor immune therapies placed within the context of tumor evolution. Clin Cancer Res; 21(6); 1258–66. ©2015 AACR..
Robert, C.
Schachter, J.
Long, G.V.
Arance, A.
Grob, J.J.
Mortier, L.
Daud, A.
Carlino, M.S.
McNeil, C.
Lotem, M.
Larkin, J.
Lorigan, P.
Neyns, B.
Blank, C.U.
Hamid, O.
Mateus, C.
Shapira-Frommer, R.
Kosh, M.
Zhou, H.
Ibrahim, N.
Ebbinghaus, S.
Ribas, A.
(2015). Pembrolizumab versus Ipilimumab in Advanced Melanoma. New england journal of medicine,
Vol.372
(26),
pp. 2521-2532.
Kasenda, B.
Larkin, J.
Gore, M.
(2015). Immunotherapies in Early and Advanced Renal Cell Cancer. ,
,
pp. 1-10.
Martin-Liberal, J.
Larkin, J.
(2015). Vemurafenib for the treatment of BRAF mutant metastatic melanoma. Future oncol,
Vol.11
(4),
pp. 579-589.
show abstract
Vemurafenib was the first selective BRAF inhibitor licensed in cancer. It is indicated for the treatment of patients affected by advanced melanoma with BRAF V600 mutation. It has shown successful results in terms of efficacy together with a favorable toxicity profile. Other compounds such as the BRAF inhibitor dabrafenib and the immunotherapeutic agent ipilimumab are also approved in the same group of patients. This article reviews the chemistry, pharmacokinetics, pharmacodynamics and clinical development of vemurafenib. Moreover, its efficacy and toxicity are compared with dabrafenib and ipilimumab. A number of trials with vemurafenib alone or in combination with other drugs are also analyzed. These trials will determine the role of vemurafenib in the treatment of BRAF mutant melanoma in forthcoming years..
Molina, A.M.
Hutson, T.E.
Larkin, J.
Gold, A.M.
Wood, K.
Carter, D.
Motzer, R.
Michaelson, M.D.
(2014). A phase 1b clinical trial of the multi-targeted tyrosine kinase inhibitor lenvatinib (E7080) in combination with everolimus for treatment of metastatic renal cell carcinoma (RCC). Cancer chemotherapy and pharmacology,
Vol.73
(1),
pp. 181-189.
Gerlinger, M.
Horswell, S.
Larkin, J.
Rowan, A.J.
Salm, M.P.
Varela, I.
Fisher, R.
McGranahan, N.
Matthews, N.
Santos, C.
Martinez, P.
Phillimore, B.
Begum, S.
Rabinowitz, A.
Spencer-Dene, B.
Gulati, S.
Bates, P.A.
Stamp, G.
Pickering, L.
Gore, M.
Nicol, D.L.
Hazell, S.
Futreal, P.A.
Stewart, A.
Swanton, C.
(2014). Genomic architecture and evolution of clear cell renal carcinomas defined by multiregion sequencing. Nature genetics,
.
show abstract
Clear cell renal carcinomas (ccRCCs) can display intratumor heterogeneity (ITH). We applied multiregion exome sequencing (M-seq) to resolve the genetic architecture and evolutionary histories of ten ccRCCs. Ultra-deep sequencing identified ITH in all cases. We found that 73–75% of identified ccRCC driver aberrations were subclonal, confounding estimates of driver mutation prevalence. ITH increased with the number of biopsies analyzed, without evidence of saturation in most tumors. Chromosome 3p loss and VHL aberrations were the only ubiquitous events. The proportion of C>T transitions at CpG sites increased during tumor progression. M-seq permits the temporal resolution of ccRCC evolution and refines mutational signatures occurring during tumor development..
Khattak, M.
Larkin, J.
(2014). Sequential therapy with targeted agents in metastatic renal cell carcinoma: beyond second-line and overcoming drug resistance. World j urol,
Vol.32
(1),
pp. 19-29.
show abstract
Renal cell carcinoma comprises 2-3% of all adult malignancies and its incidence is increasing. Overall survival of patients with advanced disease has increased over the last decade due to the development of many effective targeted agents. Unfortunately, most patients inevitably develop resistance to these agents. While our understanding of the underlying resistance mechanisms has improved, there remain multiple challenges in order to overcome resistance to targeted agents. Sequential and combination therapy with a variety of novel drugs has been evaluated to maintain ongoing clinical benefit and potentially overcome drug resistance. Retrospective data suggest that further anti-angiogenic therapy may be beneficial in advanced renal cell carcinoma after prior progression on two targeted agents with a similar or different mechanism of action. However, further randomised data are needed to better define the role of these agents beyond second-line therapy in the treatment of renal cell carcinoma..
McArthur, G.A.
Chapman, P.B.
Robert, C.
Larkin, J.
Haanen, J.B.
Dummer, R.
Ribas, A.
Hogg, D.
Hamid, O.
Ascierto, P.A.
Garbe, C.
Testori, A.
Maio, M.
Lorigan, P.
Lebbé, C.
Jouary, T.
Schadendorf, D.
O'Day, S.J.
Kirkwood, J.M.
Eggermont, A.M.
Dréno, B.
Sosman, J.A.
Flaherty, K.T.
Yin, M.
Caro, I.
Cheng, S.
Trunzer, K.
Hauschild, A.
(2014). Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet oncol,
Vol.15
(3),
pp. 323-332.
show abstract
BACKGROUND: In the BRIM-3 trial, vemurafenib was associated with risk reduction versus dacarbazine of both death and progression in patients with advanced BRAF(V600) mutation-positive melanoma. We present an extended follow-up analysis of the total population and in the BRAF(V600E) and BRAF(V600K) mutation subgroups. METHODS: Patients older than 18 years, with treatment-naive metastatic melanoma and whose tumour tissue was positive for BRAF(V600) mutations were eligible. Patients also had to have a life expectancy of at least 3 months, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate haematological, hepatic, and renal function. Patients were randomly assigned by interactive voice recognition system to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg/m(2) of body surface area intravenously every 3 weeks). Coprimary endpoints were overall survival and progression-free survival, analysed in the intention-to-treat population (n=675), with data censored at crossover. A sensitivity analysis was done. This trial is registered with ClinicalTrials.gov, NCT01006980. FINDINGS: 675 eligible patients were enrolled from 104 centres in 12 countries between Jan 4, 2010, and Dec 16, 2010. 337 patients were randomly assigned to receive vemurafenib and 338 to receive dacarbazine. Median follow-up was 12·5 months (IQR 7·7-16·0) on vemurafenib and 9·5 months (3·1-14·7) on dacarbazine. 83 (25%) of the 338 patients initially randomly assigned to dacarbazine crossed over from dacarbazine to vemurafenib. Median overall survival was significantly longer in the vemurafenib group than in the dacarbazine group (13·6 months [95% CI 12·0-15·2] vs 9·7 months [7·9-12·8]; hazard ratio [HR] 0·70 [95% CI 0·57-0·87]; p=0·0008), as was median progression-free survival (6·9 months [95% CI 6·1-7·0] vs 1·6 months [1·6-2·1]; HR 0·38 [95% CI 0·32-0·46]; p<0·0001). For the 598 (91%) patients with BRAF(V600E) disease, median overall survival in the vemurafenib group was 13·3 months (95% CI 11·9-14·9) compared with 10·0 months (8·0-14·0) in the dacarbazine group (HR 0·75 [95% CI 0·60-0·93]; p=0·0085); median progression-free survival was 6·9 months (95% CI 6·2-7·0) and 1·6 months (1·6-2·1), respectively (HR 0·39 [95% CI 0·33-0·47]; p<0·0001). For the 57 (9%) patients with BRAF(V600K) disease, median overall survival in the vemurafenib group was 14·5 months (95% CI 11·2-not estimable) compared with 7·6 months (6·1-16·6) in the dacarbazine group (HR 0·43 [95% CI 0·21-0·90]; p=0·024); median progression-free survival was 5·9 months (95% CI 4·4-9·0) and 1·7 months (1·4-2·9), respectively (HR 0·30 [95% CI 0·16-0·56]; p<0·0001). The most frequent grade 3-4 events were cutaneous squamous-cell carcinoma (65 [19%] of 337 patients) and keratoacanthomas (34 [10%]), rash (30 [9%]), and abnormal liver function tests (38 [11%]) in the vemurafenib group and neutropenia (26 [9%] of 287 patients) in the dacarbazine group. Eight (2%) patients in the vemurafenib group and seven (2%) in the dacarbazine group had grade 5 events. INTERPRETATION: Inhibition of BRAF with vemurafenib improves survival in patients with the most common BRAF(V600E) mutation and in patients with the less common BRAF(V600K) mutation. FUNDING: F Hoffmann-La Roche-Genentech..
Hutson, T.E.
Bukowski, R.M.
Rini, B.I.
Gore, M.E.
Larkin, J.M.
Figlin, R.A.
Barrios, C.H.
Escudier, B.
Lin, X.
Fly, K.
Martell, B.
Matczak, E.
Motzer, R.J.
(2014). Efficacy and safety of sunitinib in elderly patients with metastatic renal cell carcinoma. Br j cancer,
Vol.110
(5),
pp. 1125-1132.
show abstract
BACKGROUND: We retrospectively analyzed sunitinib outcome as a function of age in metastatic renal cell carcinoma (mRCC) patients. METHODS: Data were pooled from 1059 patients in six trials. Kaplan-Meier estimates of progression-free survival (PFS) and overall survival (OS) were compared by log-rank test between patients aged <70 (n=857; 81%) and ≥70 (n=202; 19%) years. RESULTS: In first-line patients, median PFS was comparable in younger and older patients, 9.9 vs 11.0 months, respectively (HR, 0.89; 95% CI: 0.73-1.09; P=0.2629), as was median OS, 23.6 vs 25.6 months (HR, 0.93; 95% CI: 0.74-1.18; P=0.5442). Similarly, in cytokine-refractory patients, median PFS was 8.1 vs 8.4 months (HR, 0.79; 95% CI: 0.49-1.28; P=0.3350), while median OS was 20.2 vs 15.8 months (HR, 1.14; 95% CI: 0.73-1.79; P=0.5657). Some treatment-emergent adverse events were significantly less common in younger vs older patients, including fatigue (60% vs 69%), cough (20% vs 29%), peripheral edema (17% vs 27%), anemia (18% vs 25%), decreased appetite (13% vs 29%), and thrombocytopenia (16% vs 25%; all P<0.05). Hand-foot syndrome was more common in younger patients (32% vs 24%). CONCLUSIONS: Advanced age should not be a deterrent to sunitinib therapy and elderly patients may achieve additional clinical benefit..
Martin-Liberal, J.
Lagares-Tena, L.
Larkin, J.
(2014). Prospects for MEK inhibitors for treating cancer. Expert opin drug saf,
Vol.13
(4),
pp. 483-495.
show abstract
INTRODUCTION: The MAPK pathway is a signaling network that plays a key role in many normal cellular processes and in a large number of human malignancies. One of its effectors, MEK, is essential for the carcinogenesis of different tumors. In recent years, several drugs able to inhibit MEK have been assessed in clinical trials. Trametinib has recently become the first MEK inhibitor licensed for cancer treatment (advanced melanoma). AREAS COVERED: We comprehensively review the safety and clinical efficacy of the family of MEK inhibitors, either alone or in combination with other drugs. We discuss data ranging from the Phase III trial of trametinib in melanoma to the most recent drugs with early signs of antitumor activity. In addition, we explain the reasons for the unsuccessful results of the early trials with MEK inhibitors and provide a view of their role in cancer treatment in forthcoming years. EXPERT OPINION: MEK inhibitors are a potentially safe and active treatment option for the treatment of many human malignancies. The information provided by a large series of studies currently ongoing will be very valuable in order to optimize their use. Adequate selection of patients is crucial for achieving successful results with these compounds..
Larkin, J.
Del Vecchio, M.
Ascierto, P.A.
Krajsova, I.
Schachter, J.
Neyns, B.
Espinosa, E.
Garbe, C.
Sileni, V.C.
Gogas, H.
Miller, W.H.
Mandalà, M.
Hospers, G.A.
Arance, A.
Queirolo, P.
Hauschild, A.
Brown, M.P.
Mitchell, L.
Veronese, L.
Blank, C.U.
(2014). Vemurafenib in patients with BRAF(V600) mutated metastatic melanoma: an open-label, multicentre, safety study. Lancet oncol,
Vol.15
(4),
pp. 436-444.
show abstract
BACKGROUND: The orally available BRAF kinase inhibitor vemurafenib, compared with dacarbazine, shows improved response rates, progression-free survival (PFS), and overall survival in patients with metastatic melanoma that has a BRAF(V600) mutation. We assessed vemurafenib in patients with advanced metastatic melanoma with BRAF(V600) mutations who had few treatment options. METHODS: In an open-label, multicentre study, patients with untreated or previously treated melanoma and a BRAF(V600) mutation received oral vemurafenib 960 mg twice a day. The primary endpoint was safety. All analyses were done on the safety population, which included all patients who received at least one dose of vemurafenib. This report is the third interim analysis of this study. This study is registered with ClinicalTrials.gov, number NCT01307397. FINDINGS: Between March 1, 2011, and Jan 31, 2013, 3226 patients were enrolled in 44 countries. 3222 patients received at least one dose of vemurafenib (safety population). At data cutoff, 868 (27%) patients were on study treatment and 2354 (73%) had withdrawn, mainly because of disease progression. Common adverse events of all grades included rash (1592 [49%]), arthralgia (1259 [39%]), fatigue (1093 [34%]), photosensitivity reaction (994 [31%]), alopecia (826 [26%]), and nausea (628 [19%]). 1480 (46%) patients reported grade 3 or 4 adverse events, including cutaneous squamous cell carcinoma (389 [12%]), rash (155 [5%]), liver function abnormalities (165 [5%]), arthralgia (106 [3%]), and fatigue (93 [3%]). Grade 3 and 4 adverse events were reported more frequently in patients aged 75 years and older (n=257; 152 [59%, 95% CI 53-65] and ten [4%, 2-7], respectively) than in those younger than 75 years (n=2965; 1286 [43%, 42-45] and 82 [3%, 2-3], respectively). INTERPRETATION: Vemurafenib safety in this diverse population of patients with BRAF(V600) mutated metastatic melanoma, who are more representative of routine clinical practice, was consistent with the safety profile shown in the pivotal trials of this drug. FUNDING: F Hoffmann-La Roche..
Turajlic, S.
Furney, S.J.
Stamp, G.
Rana, S.
Ricken, G.
Oduko, Y.
Saturno, G.
Springer, C.
Hayes, A.
Gore, M.
Larkin, J.
Marais, R.
(2014). Whole-genome sequencing reveals complex mechanisms of intrinsic resistance to BRAF inhibition. Ann oncol,
Vol.25
(5),
pp. 959-967.
show abstract
BACKGROUND: BRAF is mutated in ∼42% of human melanomas (COSMIC. http://www.sanger.ac.uk/genetics/CGP/cosmic/) and pharmacological BRAF inhibitors such as vemurafenib and dabrafenib achieve dramatic responses in patients whose tumours harbour BRAF(V600) mutations. Objective responses occur in ∼50% of patients and disease stabilisation in a further ∼30%, but ∼20% of patients present primary or innate resistance and do not respond. Here, we investigated the underlying cause of treatment failure in a patient with BRAF mutant melanoma who presented primary resistance. METHODS: We carried out whole-genome sequencing and single nucleotide polymorphism (SNP) array analysis of five metastatic tumours from the patient. We validated mechanisms of resistance in a cell line derived from the patient's tumour. RESULTS: We observed that the majority of the single-nucleotide variants identified were shared across all tumour sites, but also saw site-specific copy-number alterations in discrete cell populations at different sites. We found that two ubiquitous mutations mediated resistance to BRAF inhibition in these tumours. A mutation in GNAQ sustained mitogen-activated protein kinase (MAPK) signalling, whereas a mutation in PTEN activated the PI3 K/AKT pathway. Inhibition of both pathways synergised to block the growth of the cells. CONCLUSIONS: Our analyses show that the five metastases arose from a common progenitor and acquired additional alterations after disease dissemination. We demonstrate that a distinct combination of mutations mediated primary resistance to BRAF inhibition in this patient. These mutations were present in all five tumours and in a tumour sample taken before BRAF inhibitor treatment was administered. Inhibition of both pathways was required to block tumour cell growth, suggesting that combined targeting of these pathways could have been a valid therapeutic approach for this patient..
Kelderman, S.
Heemskerk, B.
van Tinteren, H.
van den Brom, R.R.
Hospers, G.A.
van den Eertwegh, A.J.
Kapiteijn, E.W.
de Groot, J.W.
Soetekouw, P.
Jansen, R.L.
Fiets, E.
Furness, A.J.
Renn, A.
Krzystanek, M.
Szallasi, Z.
Lorigan, P.
Gore, M.E.
Schumacher, T.N.
Haanen, J.B.
Larkin, J.M.
Blank, C.U.
(2014). Lactate dehydrogenase as a selection criterion for ipilimumab treatment in metastatic melanoma. Cancer immunology immunotherapy,
Vol.63
(5),
pp. 449-458.
Gupta, A.
Love, S.
Schuh, A.
Shanyinde, M.
Larkin, J.M.
Plummer, R.
Nathan, P.D.
Danson, S.
Ottensmeier, C.H.
Lorigan, P.
Collins, L.
Wise, A.
Asher, R.
Lisle, R.
Middleton, M.R.
(2014). DOC-MEK: a double-blind randomized phase II trial of docetaxel with or without selumetinib in wild-type BRAF advanced melanoma. Annals of oncology,
Vol.25
(5),
pp. 968-974.
Martin-Liberal, J.
Larkin, J.
(2014). New RAF kinase inhibitors in cancer therapy. Expert opin pharmacother,
Vol.15
(9),
pp. 1235-1245.
show abstract
INTRODUCTION: Alterations in some key components of the MAPK pathway, such as BRAF, have been found to be related to the development of several malignancies. A number of BRAF inhibitors have been developed in recent years. Two of these compounds, vemurafenib and dabrafenib, have been licensed for the treatment of BRAF-mutant advanced melanoma. AREAS COVERED: This article reviews the antitumour activity and safety of the BRAF inhibitors, vemurafenib and dabrafenib. Moreover, early clinical data available for the most promising new members of this family of drugs as well as the novel therapeutic strategy of dual RAF-MEK inhibition is reviewed. A perspective of the potential role of MAPK inhibition in the treatment of cancer in forthcoming years is also provided. EXPERT OPINION: Inhibition of BRAF has achieved highly successful results in patients affected by BRAF-mutated melanoma and has revolutionised their care. Its efficacy in other malignancies is currently under evaluation in monotherapy and as combination with other agents. Early clinical results of concomitant inhibition of BRAF and MEK suggest that this therapeutic approach is superior to either BRAF or MEK inhibition alone. Identification of BRAF mutations sensitive to treatment is essential for the success of these drugs..
Benson, C.
Vitfell-Rasmussen, J.
Maruzzo, M.
Fisher, C.
Tunariu, N.
Mitchell, S.
Al-Muderis, O.
Thway, K.
Larkin, J.
Judson, I.
(2014). A retrospective study of patients with malignant PEComa receiving treatment with sirolimus or temsirolimus: the Royal Marsden Hospital experience. Anticancer res,
Vol.34
(7),
pp. 3663-3668.
show abstract
UNLABELLED: Perivascular epithelioid cell tumors (PEComas) are rare tumors driven by tuberous sclerosis complex gene mutations causing up-regulation of mTOR. We report the outcome of ten consecutive patients treated with sirolimus or temsirolimus. PATIENTS AND METHODS: A retrospective analysis was performed on patients seen between 2007 and 2013. Demographic and treatment data were collected and radiological response was assessed. RESULTS: Ten patients were investigated, eight females, with median age of 47.5 years. Nine patients received sirolimus, one temsirolimus. The median treatment duration was 128 (range=7-1,366 days). Temsirolimus was given at 25 mg IV weekly and median starting dose of sirolimus was 3 mg daily. Seven patients were evaluable for response by RECIST: 5 showed partial response (50%), 1 stable disease (10%) and 1 progressive disease (10%). Two patients progressed rapidly on treatment. One patient stopped due to grade 3 hyperlipidaemia although CT scan shows maintained response. Three patients continue on treatment while the remainder stopped due to disease progression. CONCLUSION: Our study confirms that mTOR inhibition with sirolimus/temsirolimus is well-tolerated with good radiological responses, albeit short-lived, and supports its use in PEComas..
Larkin, J.
Fishman, M.
Wood, L.
Negrier, S.
Olivier, K.
Pyle, L.
Gorbunova, V.
Jonasch, E.
Andrews, L.
Staehler, M.
(2014). Axitinib for the treatment of metastatic renal cell carcinoma: recommendations for therapy management to optimize outcomes. Am j clin oncol,
Vol.37
(4),
pp. 397-403.
show abstract
Axitinib is a novel, oral, multitargeted tyrosine kinase inhibitor, which inhibits vascular endothelial growth factor receptors 1, 2, and 3 at subnanomolar concentrations in vitro. In the phase III clinical trial in patients with metastatic renal cell carcinoma, axitinib showed a high objective response rate, and significantly prolonged progression-free survival compared with sorafenib. Thus, it is the first drug that has proven the concept of sequencing tyrosine kinase inhibitors in second-line treatment in a phase III prospective randomized trial. Although generally well tolerated and associated with a low incidence of grade 3 or 4 toxicities, axitinib shows a distinct pattern of adverse events that require monitoring and management. The most common adverse events observed with axitinib include diarrhea, hypertension, fatigue, nausea, and vomiting. This article summarizes the most important adverse events observed and proposes recommendations for their monitoring, prevention, and treatment. The recommendations are based on the existing literature and discussion by an expert group of international physicians and nurses specialized in oncologic treatment of metastatic renal cell carcinoma, which gathered in July 2011 in London, UK. Proactive assessment and management of adverse events during axitinib therapy can minimize treatment interruptions and ensure optimal effect of treatment..
Fisher, R.
Horswell, S.
Rowan, A.
Salm, M.P.
de Bruin, E.C.
Gulati, S.
McGranahan, N.
Stares, M.
Gerlinger, M.
Varela, I.
Crockford, A.
Favero, F.
Quidville, V.
André, F.
Navas, C.
Grönroos, E.
Nicol, D.
Hazell, S.
Hrouda, D.
O'Brien, T.
Matthews, N.
Phillimore, B.
Begum, S.
Rabinowitz, A.
Biggs, J.
Bates, P.A.
McDonald, N.Q.
Stamp, G.
Spencer-Dene, B.
Hsieh, J.J.
Xu, J.
Pickering, L.
Gore, M.
Larkin, J.
Swanton, C.
(2014). Development of synchronous VHL syndrome tumors reveals contingencies and constraints to tumor evolution. Genome biology,
Vol.15
(8),
p. 433.
show abstract
full text
Background
Genomic analysis of multi-focal renal cell carcinomas from an individual with a germline VHL mutation offers a unique opportunity to study tumor evolution.
Results
We perform whole exome sequencing on four clear cell renal cell carcinomas removed from both kidneys of a patient with a germline VHL mutation. We report that tumors arising in this context are clonally independent and harbour distinct secondary events exemplified by loss of chromosome 3p, despite an identical genetic background and tissue microenvironment. We propose that divergent mutational and copy number anomalies are contingent upon the nature of 3p loss of heterozygosity occurring early in tumorigenesis. However, despite distinct 3p events, genomic, proteomic and immunohistochemical analyses reveal evidence for convergence upon the PI3K-AKT-mTOR signaling pathway. Four germline tumors in this young patient, and in a second, older patient with VHL syndrome demonstrate minimal intra-tumor heterogeneity and mutational burden, and evaluable tumors appear to follow a linear evolutionary route, compared to tumors from patients with sporadic clear cell renal cell carcinoma.
Conclusions
In tumors developing from a germline VHL mutation, the evolutionary principles of contingency and convergence in tumor development are complementary. In this small set of patients with early stage VHL-associated tumors, there is reduced mutation burden and limited evidence of intra-tumor heterogeneity..
Ascierto, P.A.
Larkin, J.
(2014). Advances in immunotherapy for melanoma. Melanoma management,
Vol.1
(1),
pp. 19-24.
show abstract
Paolo A Ascierto obtained his MD from the University of Naples, Italy, where he earned board certification in oncology. He is currently Director at the Unit of Melanoma, Cancer Immunotherapy and Innovative Therapy Unit, National Tumor Institute ‘Fondazione G. Pascale’, Naples, Italy. Before his present position, he served consecutive positions there as a postdoctoral fellow and then as Vice Director of the Department of Clinical Immunology. His major research interests have included genetics and proteomics research of melanoma, apoptosis and cell death in human cancer and the assessment of molecular markers for tumor progression in melanoma, as well as the management of targeted therapies for melanoma, vaccination treatments and biochemical and immunological monitoring. He has served as a principal investigator in numerous clinical trials and has been widely published in peer-reviewed journals on topics related to his interests. Ascierto has been an invited speaker at more than 200 national and international meetings and is an active member of the Italian Society of Medical Oncology (AIOM), the American Society of Clinical Oncology (ASCO), the European Society of Medical Oncology (ESMO), the European Organisation for Research and Treatment of Cancer (EORTC) and the International Society for Biological Therapy of Cancer (iSBTc). He is also the Editor-in-Chief of the Combination Strategies section of the Journal of Translational Medicine and serves as a scientific reviewer for several journals. James Larkin is a consultant medical oncologist specializing in the treatment of patients with cancer of the kidney and cancers of the skin, including melanoma. Larkin obtained a first-class degree in Natural Sciences from Cambridge University and undertook clinical training at Oxford University, qualifying in 1996. He underwent general medical training in London and, in 2001, won a Medical Research Council Fellowship for a Clinician, carrying out laboratory research at the Institute of Cancer Research (ICR), which led to the awarding of his PhD. He completed specialist training at The Royal Marsden Hospital and was appointed as a consultant in 2008. His research interests include the individualization of patient treatment in renal cancer and melanoma and the combination of novel targeted therapies for the treatment these diseases. He is the UK Chief Investigator for a number of clinical trials in melanoma and kidney cancer and has been awarded research grants from bodies including Cancer Research UK, the Wellcome Trust and the European Framework Programme 7. He is a member of the National Cancer Research Institute (NCRI) Melanoma Clinical Studies Group and Chair of both the NCRI Renal Cancer Clinical Studies Group and The Royal Marsden/ICR Committee for Clinical Research. .
Furney, S.J.
Turajlic, S.
Stamp, G.
Thomas, J.M.
Hayes, A.
Strauss, D.
Gavrielides, M.
Xing, W.
Gore, M.
Larkin, J.
Marais, R.
(2014). The mutational burden of acral melanoma revealed by whole-genome sequencing and comparative analysis. Pigment cell & melanoma research,
Vol.27
(5),
pp. 835-838.
Coupe, N.
Corrie, P.
Hategan, M.
Larkin, J.
Gore, M.E.
Gupta, A.
Wise, A.
Suter, S.
Ciria, C.
Love, S.
Collins, L.
Middleton, M.R.
(2014). A Phase 1, Dose Escalation Study of Paclitaxel with Gsk1120212 (Trametinib) for the Treatment of Advanced Melanoma. Annals of oncology,
Vol.25,
pp. iv379-iv379.
Schadendorf, D.
Amonkar, M.M.
Stroyakovskiy, D.
Levchenko, E.
Gogas, H.
De Braud, F.G.
Grob, J.
Bondarenko, I.
Garbe, C.
Lebbe, C.
Larkin, J.
Chiarion-Sileni, V.
Millward, M.
Arance, A.
Mandalà, M.
Casey, M.
Demarini, D.J.
Irani, J.
Aktan, G.
Long, G.V.
(2014). Combi-D: Quality of Life (Qol) Impact of the Combination of Dabrafenib and Trametinib (D + T) Versus Dabrafenib Monotherapy (D) in Patients with Braf V600E/K Unresectable or Metastatic Melanoma in a Phase III Trial. Annals of oncology,
Vol.25,
pp. iv377-iv377.
Gravis, G.
Chanez, B.
Derosa, L.
Beuselinck, B.
Laguerre, B.
Barthelemy, P.
Brachet, P.E.
Lobbedez, F.J.
Escudier, B.
Stewart, G.D.
Harrison, D.
Laird, A.
Vasudev, N.
Ralph, C.
Larkin, J.
Lote, H.
Walz, J.
Thomassin, J.
Salem, N.
Boher, J.M.
(2014). Impact on Overall Survival of Glandular Metastasis in Patients with Metastatic Clear Cell Renal Cell Carcinoma on Behalf of the Renal Cross Channel Group. Annals of oncology,
Vol.25,
pp. iv286-iv286.
Larkin, J.
Okines, A.
(2014). Precision Medicine in Kidney Cancer and Clinical Trial Designs. Annals of oncology,
Vol.25,
pp. iv17-iv17.
Nobbenhuis, M.A.
Lalondrelle, S.
Larkin, J.
Banerjee, S.
(2014). Management of melanomas of the gynaecological tract. Curr opin oncol,
Vol.26
(5),
pp. 508-513.
show abstract
PURPOSE OF REVIEW: Primary melanomas originating from the gynaecological tract are rare and aggressive cancers. The 5-year survival is around 10%. The majority of tumours differ from cutaneous melanomas, which arise from the skin, by developing from melanocytes located in mucosal epithelium. The clinical behaviour, prognosis and the biology of mucosal melanomas are distinct from cutaneous melanomas. In this article, we summarize the current management of melanomas of the gynaecological tract (vulva, vagina, ovary and cervix) and discuss the progress in developing new treatments. RECENT FINDINGS: The management of mucosal melanomas has not changed substantially over the last decade and the prognosis remains poor. Surgery remains the primary treatment of choice in all localized melanomas of the genital tract. Radiotherapy and chemotherapy are options but have limited success for the majority of women. Activation of c-KIT occurs in vulvar melanomas. Clinical trials of targeted agents are underway. SUMMARY: As a result of the rarity of gynaecological tract melanomas, challenges associated with their anatomical locations and resistance to conventional radiotherapy and chemotherapy, this group of conditions remain difficult to treat and continue to have a poor prognosis. A greater understanding of the molecular profile of these cancers may provide promising targeted approaches..
Pickering, L.
Larkin, J.
(2014). Systemic anti-cancer therapy (SACT) dataset. The lancet oncology,
Vol.15
(10),
pp. 1063-1063.
Leijen, S.
Barlesi, F.
Eberhardt, W.E.
Martinez, G.M.
Dieras, V.
Schellens, J.H.
Middleton, M.
Calvo, E.
Paz-Ares, L.
Larkin, J.
Jodrell, D.
Soria, J.C.
(2014). OCULAR TOXICITIES OBSERVED WITH MEK INHIBITOR RO4987655 (CH4987655) IN A SINGLE AGENT PHASE I STUDY WITH EXTENSION IN PATIENTS WITH ADVANCED SOLID TUMORS. British journal of clinical pharmacology,
Vol.78
(4),
pp. 769-769.
Thian, Y.
Gutzeit, A.
Koh, D.-.
Fisher, R.
Lote, H.
Larkin, J.
Sohaib, A.
(2014). Revised Choi imaging criteria correlate with clinical outcomes in patients with metastatic renal cell carcinoma treated with sunitinib. Radiology,
Vol.273
(2),
pp. 452-461.
show abstract
PURPOSE: To compare revised Choi criteria that incorporate concurrent size and attenuation changes at early follow-up imaging with Response Evaluation Criteria in Solid Tumors ( RECIST Response Evaluation Criteria in Solid Tumors ) 1.1 and original Choi criteria in stratification of clinical outcomes in patients with metastatic renal cell carcinoma ( mRCC metastatic renal cell carcinoma ) treated with sunitinib. MATERIALS AND METHODS: Institutional review board approved this retrospective study and waived informed consent. Baseline and first follow-up computed tomographic scans in 69 patients (50 men, 19 women; mean age, 60.3 years; range, 19-83 years) with mRCC metastatic renal cell carcinoma treated with sunitinib from October 1, 2008, to March 1, 2013, were evaluated for tumor response by using RECIST Response Evaluation Criteria in Solid Tumors 1.1, original Choi criteria, and revised Choi criteria. Correlations with overall survival ( OS overall survival ) and progression-free survival ( PFS progression-free survival ) were compared and stratified according to each radiologic criteria with Kaplan-Meier and multivariate Cox regression analysis. RESULTS: Median follow-up time was 29.7 months (95% confidence interval [ CI confidence interval ]: 18.9, 45.9). Response according to revised Choi criteria was independently correlated with OS overall survival (hazard ratio, 0.47 [95% CI confidence interval : 0.23, 0.99]; P = .046) and PFS progression-free survival (hazard ratio, 0.53 [95% CI confidence interval : 0.29, 0.99]; P = .047). Response according to RECIST Response Evaluation Criteria in Solid Tumors was not significantly correlated with OS overall survival (hazard ratio, 0.65 [95% CI confidence interval : 0.27, 1.58]; P = .344) or PFS progression-free survival (hazard ratio, 0.89 [95% CI confidence interval : 0.42, 1.91]; P = .768). Response according to original Choi criteria was not significantly correlated with OS overall survival (hazard ratio, 0.60 [95% CI confidence interval : 0.32, 1.11]; P = .106) or PFS progression-free survival (hazard ratio, 0.59 [95% CI confidence interval : 0.34, 1.02]; P = .060). Median OS overall survival and PFS progression-free survival in responders according to revised Choi criteria was 39.4 months (95% CI confidence interval : 9.1, upper limit not estimated) and 13.7 months (95% CI confidence interval : 6.4, 24.6), respectively, compared with 12.8 months (95% CI confidence interval : 8.7, 18.0) and 5.3 months (95% CI confidence interval : 3.9, 8.4), respectively, in nonresponders. CONCLUSION: Contemporaneous reduction in tumor size and attenuation were correlated with favorable clinical outcomes. Response according to revised Choi criteria showed better correlation with clinical outcomes compared with that according to RECIST Response Evaluation Criteria in Solid Tumors or original Choi criteria in patients with mRCC metastatic renal cell carcinoma treated with sunitinib..
Kenny, L.M.
Tomasi, G.
Turkheimer, F.
Larkin, J.
Gore, M.
Brock, C.S.
Mangar, S.
Aboagye, E.O.
(2014). Preliminary clinical assessment of the relationship between tumor alphavbeta3 integrin and perfusion in patients studied with [18F]fluciclatide kinetics and [15O]H2O PET. Ejnmmi research,
Vol.4
(1).
Larkin, J.
Ascierto, P.A.
Dréno, B.
Atkinson, V.
Liszkay, G.
Maio, M.
Mandalà, M.
Demidov, L.
Stroyakovskiy, D.
Thomas, L.
de la Cruz-Merino, L.
Dutriaux, C.
Garbe, C.
Sovak, M.A.
Chang, I.
Choong, N.
Hack, S.P.
McArthur, G.A.
Ribas, A.
(2014). Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N engl j med,
Vol.371
(20),
pp. 1867-1876.
show abstract
BACKGROUND: The combined inhibition of BRAF and MEK is hypothesized to improve clinical outcomes in patients with melanoma by preventing or delaying the onset of resistance observed with BRAF inhibitors alone. This randomized phase 3 study evaluated the combination of the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib. METHODS: We randomly assigned 495 patients with previously untreated unresectable locally advanced or metastatic BRAF V600 mutation-positive melanoma to receive vemurafenib and cobimetinib (combination group) or vemurafenib and placebo (control group). The primary end point was investigator-assessed progression-free survival. RESULTS: The median progression-free survival was 9.9 months in the combination group and 6.2 months in the control group (hazard ratio for death or disease progression, 0.51; 95% confidence interval [CI], 0.39 to 0.68; P<0.001). The rate of complete or partial response in the combination group was 68%, as compared with 45% in the control group (P<0.001), including rates of complete response of 10% in the combination group and 4% in the control group. Progression-free survival as assessed by independent review was similar to investigator-assessed progression-free survival. Interim analyses of overall survival showed 9-month survival rates of 81% (95% CI, 75 to 87) in the combination group and 73% (95% CI, 65 to 80) in the control group. Vemurafenib and cobimetinib was associated with a nonsignificantly higher incidence of adverse events of grade 3 or higher, as compared with vemurafenib and placebo (65% vs. 59%), and there was no significant difference in the rate of study-drug discontinuation. The number of secondary cutaneous cancers decreased with the combination therapy. CONCLUSIONS: The addition of cobimetinib to vemurafenib was associated with a significant improvement in progression-free survival among patients with BRAF V600-mutated metastatic melanoma, at the cost of some increase in toxicity. (Funded by F. Hoffmann-La Roche/Genentech; coBRIM ClinicalTrials.gov number, NCT01689519.)..
Long, G.V.
Stroyakovskiy, D.
Gogas, H.
Levchenko, E.
de Braud, F.
Larkin, J.
Garbe, C.
Jouary, T.
Hauschild, A.
Grob, J.J.
Sileni, V.C.
Lebbe, C.
Mandala, M.
Millward, M.
Arance, A.
Bondarenko, I.
Haanen, J.B.
Hansson, J.
Utikal, J.
Ferraresi, V.
Kovalenko, N.
Mohr, P.
Probachai, V.
Schadendorf, D.
Nathan, P.
Robert, C.
Ribas, A.
DeMarini, D.J.
Irani, J.G.
Casey, M.
Ouellet, D.
Martin, A.-.
Le, N.
Patel, K.
Flaherty, K.
(2014). Combined BRAF and MEK Inhibition versus BRAF Inhibition Alone in Melanoma. New england journal of medicine,
Vol.371
(20),
pp. 1877-1888.
Antonia, S.J.
Larkin, J.
Ascierto, P.A.
(2014). Immuno-oncology combinations: a review of clinical experience and future prospects. Clin cancer res,
Vol.20
(24),
pp. 6258-6268.
show abstract
Immuno-oncology is an evolving treatment modality that includes immunotherapies designed to harness the patient's own immune system. This approach is being studied for its potential to improve long-term survival across multiple tumor types. It is now important to determine how immunotherapies may be most effectively used to achieve the best possible patient outcomes. Combining or sequencing immunotherapies that target distinct immune pathways is a logical approach, with the potential to further enhance the magnitude of the antitumor immune response over single agents. Early clinical data in patients with melanoma treated with two immune checkpoint inhibitors, ipilimumab and nivolumab, suggest support for this combination approach. Numerous other combination approaches are being evaluated in early-phase clinical trials; however, their clinical activity remains unknown. Clinical experience to date has shown that when combining an immuno-oncology agent with an existing therapeutic modality, it is important to determine the optimal dose, schedule, and sequence..
Zimmer, L.
Barlesi, F.
Martinez-Garcia, M.
Dieras, V.
Schellens, J.H.
Spano, J.-.
Middleton, M.R.
Calvo, E.
Paz-Ares, L.
Larkin, J.
Pacey, S.
Venturi, M.
Kraeber-Bodéré, F.
Tessier, J.J.
Eberhardt, W.E.
Paques, M.
Guarin, E.
Meresse, V.
Soria, J.-.
(2014). Phase I expansion and pharmacodynamic study of the oral MEK inhibitor RO4987655 (CH4987655) in selected patients with advanced cancer with RAS-RAF mutations. Clin cancer res,
Vol.20
(16),
pp. 4251-4261.
show abstract
PURPOSE: This phase I expansion study assessed safety, pharmacodynamic effects, and antitumor activity of RO4987655, a pure MEK inhibitor, in selected patients with advanced solid tumor. EXPERIMENTAL DESIGN: We undertook a multicenter phase I two-part study (dose escalation and cohort expansion). Here, we present the part 2 expansion that included melanoma, non-small cell lung cancer (NSCLC), and colorectal cancer with oral RO4987655 administered continuously at recommended doses of 8.5 mg twice daily until progressive disease (PD). Sequential tumor sampling investigated multiple markers of pathway activation/tumor effects, including ERK phosphorylation and Ki-67 expression. BRAF and KRAS testing were implemented as selection criteria and broader tumor mutational analysis added. RESULTS: Ninety-five patients received RO4987655, including 18 BRAF-mutant melanoma, 23 BRAF wild-type melanoma, 24 KRAS-mutant NSCLC, and 30 KRAS-mutant colorectal cancer. Most frequent adverse events were rash, acneiform dermatitis, and gastrointestinal disorders, mostly grade 1/2. Four (24%) of 17 BRAF-mutated melanoma had partial response as did four (20%) of 20 BRAF wild-type melanoma and two (11%) of 18 KRAS-mutant NSCLC. All KRAS-mutant colorectal cancer developed PD. Paired tumor biopsies demonstrated reduced ERK phosphorylation among all cohorts but significant differences among cohorts in Ki-67 modulation. Sixty-nine percent showed a decrease in fluorodeoxyglucose uptake between baseline and day 15. Detailed mutational profiling confirmed RAS/RAF screening and identified additional aberrations (NRAS/non-BRAF melanomas; PIK3CA/KRAS colorectal cancer) without therapeutic implications. CONCLUSIONS: Safety profile of RO4987655 was comparable with other MEK inhibitors. Single-agent activity was observed in all entities except colorectal cancer. Evidence of target modulation and early biologic activity was shown among all indications independent of mutational status. Clin Cancer Res; 20(16); 4251-61. ©2014 AACR..
Sanchez-Laorden, B.
Viros, A.
Girotti, M.R.
Pedersen, M.
Saturno, G.
Zambon, A.
Niculescu-Duvaz, D.
Turajlic, S.
Hayes, A.
Gore, M.
Larkin, J.
Lorigan, P.
Cook, M.
Springer, C.
Marais, R.
(2014). BRAF Inhibitors Induce Metastasis in RAS Mutant or Inhibitor-Resistant Melanoma Cells By Reactivating MEK and ERK Signaling. Science signaling,
Vol.7
(318).
Ascierto, P.A.
Grimaldi, A.M.
Anderson, A.C.
Bifulco, C.
Cochran, A.
Garbe, C.
Eggermont, A.M.
Faries, M.
Ferrone, S.
Gershenwald, J.E.
Gajewski, T.F.
Halaban, R.
Hodi, F.S.
Kefford, R.
Kirkwood, J.M.
Larkin, J.
Leachman, S.
Maio, M.
Marais, R.
Masucci, G.
Melero, I.
Palmieri, G.
Puzanov, I.
Ribas, A.
Saenger, Y.
Schilling, B.
Seliger, B.
Stroncek, D.
Sullivan, R.
Testori, A.
Wang, E.
Ciliberto, G.
Mozzillo, N.
Marincola, F.M.
Thurin, M.
(2014). Future perspectives in melanoma research: meeting report from the "Melanoma Bridge", Napoli, December 5th-8th 2013. Journal of translational medicine,
Vol.12.
Khattak, M.A.
Bakr, F.
Krzystanek, M.
Szallasi, Z.
Gerlinger, M.
Santos, C.
Swanton, C.
Pickering, L.M.
Gore, M.E.
Larkin, J.M.
(2013). Prognostic and predictive markers in metastatic renal cell carcinoma. J clin oncol,
Vol.31
(7),
pp. 971-972.
Sinha, R.
Edmonds, K.
Newton-Bishop, J.
Gore, M.
Larkin, J.
Fearfield, L.
(2013). Erythema Nodosum-Like Panniculitis in Patients With Melanoma Treated With Vemurafenib. Journal of clinical oncology,
Vol.31
(19),
pp. E320-E321.
Larkin, J.
Paine, A.
Tumur, I.
Cappelleri, J.C.
Healey, P.J.
Foley, G.
Mitchell, S.
Kroes, M.
Chen, C.
(2013). Second-line treatments for the management of advanced renal cell carcinoma: systematic review and meta-analysis. Expert opin pharmacother,
Vol.14
(1),
pp. 27-39.
show abstract
OBJECTIVES: A systematic review/meta-analysis was conducted to assess the effectiveness and safety of second-line treatments for advanced renal cell carcinoma (RCC), which includes the vascular endothelial growth factor inhibitor axitinib. METHODS: Database searches were conducted to identify randomised controlled trials (RCTs). Indirect comparisons using a fixed-effect Bayesian model were used to assess the relative effectiveness of treatments and reported as hazard ratio (HR) and 95% credible intervals (CrI). RESULTS: Although 24 RCTs met eligibility criteria, only three studies were included in the fixed-effect Bayesian meta-analysis, due to differences in patient inclusion criteria/reported outcomes in the wider dataset. Robust meta-analysis was restricted to the subgroup pretreated with cytokines. In terms of progression-free survival (PFS), axitinib was superior compared with placebo (HR = 0.25, 95% CrI: 0.17 - 0.38), sorafenib (HR = 0.46, 95% CrI: 0.32 - 0.68) and pazopanib (HR = 0.47, 95% CrI: 0.26 - 0.85). An analysis including all patients, regardless of previous first-line treatment, reported similar results. There was no significant difference in PFS between sorafenib and pazopanib. CONCLUSION: Results from the present study suggest that axitinib will be an important treatment option to extend PFS in the management of advanced RCC in the second-line setting. Ongoing research will define the optimal treatment algorithm leading to a patient-focused treatment strategy..
Khattak, M.A.
Fisher, R.
Hughes, P.
Gore, M.
Larkin, J.
(2013). Ipilimumab activity in advanced uveal melanoma. Melanoma res,
Vol.23
(1),
pp. 79-81.
show abstract
Uveal melanoma (UM) is a rare disease with a distinct molecular profile. About half of the patients with UM eventually develop metastatic disease. The prognosis of these patients remains poor. Treatment options are limited and none of them have been able to show a survival benefit. Ipilimumab was the first agent to show a survival benefit in patients with cutaneous melanoma in a randomized trial; however, there is limited published evidence for its role in the management of advanced UM. Here, we report our experience of ipilimumab in five patients with advanced UM treated at an academic cancer centre in the UK. Two patients had durable stable disease and three developed progressive disease. Of the patients with stable disease, one maintained disease control at 11 months from the commencement of treatment with ∼10% reduction in tumour volume compared with the baseline, and the second patient progressed after 15 months. We also examined the tumour kinetics and response patterns that resembled that of ipilimumab in cutaneous melanoma. Given the lack of randomized trial data, our findings indicate that ipilimumab might be a reasonable treatment option for patients with advanced UM..
Fisher, R.
Gore, M.
Larkin, J.
(2013). Current and future systemic treatments for renal cell carcinoma. Semin cancer biol,
Vol.23
(1),
pp. 38-45.
show abstract
Systemic treatment of renal cell carcinoma has changed dramatically since 2007, with the development and approval of six new agents, which target complex molecular pathways regulating tumour angiogenesis and cell proliferation and survival. These treatments have significantly improved survival times in metastatic renal cell carcinoma, but remain palliative. A number of newer agents are in clinical development, which offer theoretical advantages over existing treatments, and research methodologies are adapting with the aim of defining an individualised approach to therapy which exploits the underlying tumour biology. This review will provide an overview of current and emerging systemic treatments and how they might be integrated with surgical therapy, with a particular focus on advanced, clear cell metastatic renal cell carcinoma..
Girotti, M.R.
Pedersen, M.
Sanchez-Laorden, B.
Viros, A.
Turajlic, S.
Niculescu-Duvaz, D.
Zambon, A.
Sinclair, J.
Hayes, A.
Gore, M.
Lorigan, P.
Springer, C.
Larkin, J.
Jorgensen, C.
Marais, R.
(2013). Inhibiting EGF receptor or SRC family kinase signaling overcomes BRAF inhibitor resistance in melanoma. Cancer discov,
Vol.3
(2),
pp. 158-167.
show abstract
UNLABELLED: We generated cell lines resistant to BRAF inhibitors and show that the EGF receptor (EGFR)-SRC family kinase (SFK)-STAT3 signaling pathway was upregulated in these cells. In addition to driving proliferation of resistant cells, this pathway also stimulated invasion and metastasis. EGFR inhibitors cooperated with BRAF inhibitors to block the growth of the resistant cells in vitro and in vivo, and monotherapy with the broad specificity tyrosine kinase inhibitor dasatinib blocked growth and metastasis in vivo. We analyzed tumors from patients with intrinsic or acquired resistance to vemurafenib and observed increased EGFR and SFK activity. Furthermore, dasatinib blocked the growth and metastasis of one of the resistant tumors in immunocompromised mice. Our data show that BRAF inhibitor-mediated activation of EGFR-SFK-STAT3 signaling can mediate resistance in patients with BRAF-mutant melanoma. We describe 2 treatments that seem to overcome this resistance and could deliver therapeutic efficacy in patients with drug-resistant BRAF-mutant melanoma. SIGNIFICANCE: Therapies that target the driver oncogenes in cancer can achieve remarkable responses if patients are stratified for treatment. However, as with conventional therapies, patients often develop acquired resistance to targeted therapies, and a proportion of patients are intrinsically resistant and fail to respond despite the presence of an appropriate driver oncogene mutation. We found that the EGFR/SFK pathway mediated resistance to vemurafenib in BRAF -mutant melanoma and that BRAF and EGFR or SFK inhibition blocked proliferation and invasion of these resistant tumors, providing potentially effective therapeutic options for these patients..
Khattak, M.
Fisher, R.
Turajlic, S.
Larkin, J.
(2013). Targeted therapy and immunotherapy in advanced melanoma: an evolving paradigm. Ther adv med oncol,
Vol.5
(2),
pp. 105-118.
show abstract
Metastatic melanoma is one of the most challenging malignancies to treat and often has a poor outcome. Until recently, systemic treatment options were limited, with poor response rates and no survival advantage. However, the treatment of metastatic melanoma has been revolutionized by developments in targeted therapy and immunotherapy; the BRAF inhibitor, vemurafenib, and anticytotoxic T-lymphocyte antigen 4 antibody, ipilimumab, are the first agents to demonstrate a survival benefit. Despite the success of these treatments, most patients eventually progress, and research into response and resistance mechanisms, rationally designed combination therapies and evaluation of the role of these agents in the adjuvant setting is critically important..
Ascierto, P.A.
Grimaldi, A.M.
Acquavella, N.
Borgognoni, L.
Calabro, L.
Cascinelli, N.
Cesano, A.
Del Vecchio, M.
Eggermont, A.M.
Faries, M.
Ferrone, S.
Fox, B.A.
Gajewski, T.F.
Galon, J.
Gnjatic, S.
Gogas, H.
Kashani-Sabet, M.
Kaufman, H.L.
Larkin, J.
Lo, R.S.
Mantovani, A.
Margolin, K.
Melief, C.
McArthur, G.
Palmieri, G.
Puzanov, I.
Ribas, A.
Seliger, B.
Sosman, J.
Suenaert, P.
Tarhini, A.A.
Trinchieri, G.
Vidal-Vanaclocha, F.
Wang, E.
Ciliberto, G.
Mozzillo, N.
Marincola, F.M.
Thurin, M.
(2013). Future perspectives in melanoma research Meeting report from the "Melanoma Bridge Napoli, December 2nd-4th 2012". Journal of translational medicine,
Vol.11.
Fearfield, L.
Newton-Bishop, J.A.
Sinha, R.
Edmonds, K.
Gore, M.E.
Larkin, J.
(2013). Second primary melanomas on treatment with vemurafenib: reply from the authors. Br j dermatol,
Vol.168
(4),
pp. 888-889.
Turajlic, S.
Ali, Z.
Yousaf, N.
Larkin, J.
(2013). Phase I/II RAF kinase inhibitors in cancer therapy. Expert opin investig drugs,
Vol.22
(6),
pp. 739-749.
show abstract
INTRODUCTION: Aberrant activation of RAF signalling is a frequent finding in human cancers. BRAF is the only RAF family member that is commonly mutated, whilst CRAF and ARAF play important roles in the signal transduction from mutant RAS. BRAF-specific inhibitors have been more effective in the treatment of BRAF-mutant melanoma than BRAF-mutant thyroid and colorectal cancers. AREAS COVERED: The review summarises the experience with RAF kinase inhibitors, including efficacy, modes of acquired resistance, and the mechanism behind the progression of pre-malignant RAS-mutant lesions observed with RAF kinase inhibitors. The authors review all the completed and ongoing Phase I or II clinical trials of RAF kinase inhibitors and discuss in detail the rationale behind the combinatorial approaches. EXPERT OPINION: The success of RAF kinase inhibitors has demonstrated the necessity of genotype-driven treatment selection for cancer patients. The spectrum of responses in different tumour types is explained by feedback events that are determined by cell lineage. Dissection of these events and the mechanisms of acquired resistance will determine the appropriate combination therapies. Ongoing characterisation of RAS-MAPK regulation in malignant cells may aid the development of novel agents that have greater potency for the inhibition of activated RAF kinase, and lesser propensity for promotion of RAS-mutant tumours..
Furney, S.J.
Turajlic, S.
Stamp, G.
Nohadani, M.
Carlisle, A.
Thomas, J.M.
Hayes, A.
Strauss, D.
Gore, M.
van den Oord, J.
Larkin, J.
Marais, R.
(2013). Genome sequencing of mucosal melanomas reveals that they are driven by distinct mechanisms from cutaneous melanoma. J pathol,
Vol.230
(3),
pp. 261-269.
show abstract
Mucosal melanoma displays distinct clinical and epidemiological features compared to cutaneous melanoma. Here we used whole genome and whole exome sequencing to characterize the somatic alterations and mutation spectra in the genomes of ten mucosal melanomas. We observed somatic mutation rates that are considerably lower than occur in sun-exposed cutaneous melanoma, but comparable to the rates seen in cancers not associated with exposure to known mutagens. In particular, the mutation signatures are not indicative of ultraviolet light- or tobacco smoke-induced DNA damage. Genes previously reported as mutated in other cancers were also mutated in mucosal melanoma. Notably, there were substantially more copy number and structural variations in mucosal melanoma than have been reported in cutaneous melanoma. Thus, mucosal and cutaneous melanomas are distinct diseases with discrete genetic features. Our data suggest that different mechanisms underlie the genesis of these diseases and that structural variations play a more important role in mucosal than in cutaneous melanomagenesis..
Martinez, P.
Birkbak, N.J.
Gerlinger, M.
McGranahan, N.
Burrell, R.A.
Rowan, A.J.
Joshi, T.
Fisher, R.
Larkin, J.
Szallasi, Z.
Swanton, C.
(2013). Parallel evolution of tumour subclones mimics diversity between tumours. J pathol,
Vol.230
(4),
pp. 356-364.
show abstract
Intratumour heterogeneity (ITH) may foster tumour adaptation and compromise the efficacy of personalized medicine approaches. The scale of heterogeneity within a tumour (intratumour heterogeneity) relative to genetic differences between tumours (intertumour heterogeneity) is unknown. To address this, we obtained 48 biopsies from eight stage III and IV clear cell renal cell carcinomas (ccRCCs) and used DNA copy-number analyses to compare biopsies from the same tumour with 440 single tumour biopsies from the Cancer Genome Atlas (TCGA). Unsupervised hierarchical clustering of TCGA and multi-region ccRCC samples revealed segregation of samples from the same tumour into unrelated clusters; 25% of multi-region samples appeared more similar to unrelated samples than to any other sample originating from the same tumour. We found that the majority of recurrent DNA copy number driver aberrations in single biopsies were not present ubiquitously in late-stage ccRCCs and were likely to represent subclonal events acquired during tumour progression. Such heterogeneous subclonal genetic alterations within individual tumours may impair the identification of robust ccRCC molecular subtypes classified by distinct copy number alterations and clinical outcomes. The co-existence of distinct subclonal copy number events in different regions of individual tumours reflects the diversification of individual ccRCCs through multiple evolutionary routes and may contribute to tumour sampling bias and impact upon tumour progression and clinical outcome..
Fisher, R.
Larkin, J.
(2013). Individualising treatment choices in a crowded treatment algorithm. European journal of cancer supplements,
Vol.11
(2),
pp. 160-168.
Ali, Z.
Yousaf, N.
Larkin, J.
(2013). Melanoma epidemiology, biology and prognosis. European journal of cancer supplements,
Vol.11
(2),
pp. 81-91.
Gerlinger, M.
Quezada, S.A.
Peggs, K.S.
Furness, A.J.
Fisher, R.
Marafioti, T.
Shende, V.H.
McGranahan, N.
Rowan, A.J.
Hazell, S.
Hamm, D.
Robins, H.S.
Pickering, L.
Gore, M.
Nicol, D.L.
Larkin, J.
Swanton, C.
(2013). Ultra-deep T cell receptor sequencing reveals the complexity and intratumour heterogeneity of T cell clones in renal cell carcinomas. J pathol,
Vol.231
(4),
pp. 424-432.
show abstract
The recognition of cancer cells by T cells can impact upon prognosis and be exploited for immunotherapeutic approaches. This recognition depends on the specific interaction between antigens displayed on the surface of cancer cells and the T cell receptor (TCR), which is generated by somatic rearrangements of TCR α- and β-chains (TCRb). Our aim was to assess whether ultra-deep sequencing of the rearranged TCRb in DNA extracted from unfractionated clear cell renal cell carcinoma (ccRCC) samples can provide insights into the clonality and heterogeneity of intratumoural T cells in ccRCCs, a tumour type that can display extensive genetic intratumour heterogeneity (ITH). For this purpose, DNA was extracted from two to four tumour regions from each of four primary ccRCCs and was analysed by ultra-deep TCR sequencing. In parallel, tumour infiltration by CD4, CD8 and Foxp3 regulatory T cells was evaluated by immunohistochemistry and correlated with TCR-sequencing data. A polyclonal T cell repertoire with 367-16 289 (median 2394) unique TCRb sequences was identified per tumour region. The frequencies of the 100 most abundant T cell clones/tumour were poorly correlated between most regions (Pearson correlation coefficient, -0.218 to 0.465). 3-93% of these T cell clones were not detectable across all regions. Thus, the clonal composition of T cell populations can be heterogeneous across different regions of the same ccRCC. T cell ITH was higher in tumours pretreated with an mTOR inhibitor, which could suggest that therapy can influence adaptive tumour immunity. These data show that ultra-deep TCR-sequencing technology can be applied directly to DNA extracted from unfractionated tumour samples, allowing novel insights into the clonality of T cell populations in cancers. These were polyclonal and displayed ITH in ccRCC. TCRb sequencing may shed light on mechanisms of cancer immunity and the efficacy of immunotherapy approaches..
Yousaf, N.
Larkin, J.
(2013). Axitinib in advanced renal-cell carcinoma. Lancet oncol,
Vol.14
(13),
pp. 1245-1246.
Henrion, M.
Frampton, M.
Scelo, G.
Purdue, M.
Ye, Y.
Broderick, P.
Ritchie, A.
Kaplan, R.
Meade, A.
McKay, J.
Johansson, M.
Lathrop, M.
Larkin, J.
Rothman, N.
Wang, Z.
Chow, W.-.
Stevens, V.L.
Ryan Diver, W.
Gapstur, S.M.
Albanes, D.
Virtamo, J.
Wu, X.
Brennan, P.
Chanock, S.
Eisen, T.
Houlston, R.S.
(2013). Common variation at 2q22 3 (ZEB2) influences the risk of renal cancer. Hum mol genet,
Vol.22
(4),
pp. 825-831.
show abstract
Genome-wide association studies (GWASs) of renal cell cancer (RCC) have identified four susceptibility loci thus far. To identify an additional RCC common susceptibility locus, we conducted a GWAS and performed a meta-analysis with published GWASs (totalling 2215 cases and 8566 controls of European background) and followed up the most significant association signals [nine single nucleotide polymorphisms (SNPs) in eight genomic regions] in 3739 cases and 8786 controls. A combined analysis identified a novel susceptibility locus mapping to 2q22.3 marked by rs12105918 (P = 1.80 × 10(-8); odds ratio 1.29, 95% CI: 1.18-1.41). The signal localizes to intron 2 of the ZEB2 gene (zinc finger E box-binding homeobox 2). Our findings suggest that genetic variation in ZEB2 influences the risk of RCC. This finding provides further insights into the genetic and biological basis of inherited genetic susceptibility to RCC..
Vasudev, N.S.
Goh, V.
Juttla, J.K.
Thompson, V.L.
Larkin, J.M.
Gore, M.
Nathan, P.D.
Reynolds, A.R.
(2013). Changes in tumour vessel density upon treatment with anti-angiogenic agents: relationship with response and resistance to therapy. British journal of cancer,
Vol.109
(5).
Karapanagiotou, E.M.
Roulstone, V.
Twigger, K.
Ball, M.
Tanay, M.
Nutting, C.
Newbold, K.
Gore, M.E.
Larkin, J.
Syrigos, K.N.
Coffey, M.
Thompson, B.
Mettinger, K.
Vile, R.G.
Pandha, H.S.
Hall, G.D.
Melcher, A.A.
Chester, J.
Harrington, K.J.
(2012). Phase I/II trial of carboplatin and paclitaxel chemotherapy in combination with intravenous oncolytic reovirus in patients with advanced malignancies. Clin cancer res,
Vol.18
(7),
pp. 2080-2089.
show abstract
PURPOSE: Reovirus type 3 Dearing (RT3D) replicates preferentially in Ras-activated cancers. RT3D shows synergistic in vitro cytotoxicity in combination with platins and taxanes. The purpose of this phase I/II study was to assess RT3D combined with carboplatin/paclitaxel in patients with advanced cancers. EXPERIMENTAL DESIGN: Patients were initially treated in a dose-escalating, phase I trial with intravenous RT3D days 1 to 5, carboplatin [area under curve (AUC) 5, day 1] and paclitaxel (175 mg/m(2), day 1) 3-weekly. RT3D was escalated through three dose levels: 3 × 10(9), 1 × 10(10), and 3 × 10(10) TCID(50) in cohorts of three. Primary endpoints were to define the maximum tolerated dose and dose-limiting toxicity and to recommend a dose for phase II studies. Secondary endpoints included pharmacokinetics, immune response, and antitumor activity. A subsequent phase II study using the 3 × 10(10) TCID(50) dose characterized the response rate in patients with head and neck cancer. RESULTS: Thirty-one heavily pretreated patients received study therapy. There were no dose-limiting toxicities during dose-escalation and most toxicities were grade I/II. Overall effectiveness rates were as follows: one patient had a complete response (3.8%), six patients (23.1%) had partial response, two patients (7.6%) had major clinical responses clinically evaluated in radiation pretreated lesions which are not evaluable by Response Evaluation Criteria in Solid Tumors (RECIST), nine patients (34.6%) had stable disease, and eight patients (30.8%) had disease progression. Viral shedding was minimal and antiviral immune responses were attenuated compared with previous single-agent data for RT3D. CONCLUSIONS: The combination of RT3D plus carboplatin/paclitaxel is well tolerated with evidence of activity in cancer of the head and neck. A randomized phase III study is currently open for recruitment..
Pacey, S.
Gore, M.
Chao, D.
Banerji, U.
Larkin, J.
Sarker, S.
Owen, K.
Asad, Y.
Raynaud, F.
Walton, M.
Judson, I.
Workman, P.
Eisen, T.
(2012). A Phase II trial of 17-allylamino, 17-demethoxygeldanamycin (17-AAG, tanespimycin) in patients with metastatic melanoma. Invest new drugs,
Vol.30
(1),
pp. 341-349.
show abstract
PURPOSE: A Phase II study to screen for anti-melanoma activity of the heat shock protein 90 (HSP90) inhibitor, 17-AAG (17-allylamino-17-demethoxygeldanamycin) was performed. The primary endpoint was the rate of disease stabilisation in patients with progressive, metastatic melanoma treated with 17-AAG. Secondary endpoints were to determine: the toxicity of 17-AAG, the duration of response(s), median survival and further study the pharmacokinetics and pharmacodynamics of 17-AAG. PATIENTS AND METHODS: Patients with metastatic melanoma (progressive disease documented ≤6 months of entering study) were treated with weekly, intravenous 17-AAG. A Simon one sample two stage minimax design was used. A stable disease rate of ≥25% at 6 months was considered compatible with 17-AAG having activity. RESULTS: Fourteen patients (8 male: 6 female) were entered, eleven received 17-AAG (performance status 0 or 1). Median age was 60 (range 29-81) years. The majority (93%) received prior chemotherapy and had stage M1c disease (71%). Toxicity was rarely ≥ Grade 2 in severity and commonly included fatigue, headache and gastrointestinal disturbances. One of eleven patients treated with 17-AAG had stable disease for 6 months and median survival for all patients was 173 days. The study was closed prematurely prior to completion of the first stage of recruitment and limited planned pharmacokinetic and pharmacodynamic analyses. CONCLUSION: Some evidence of 17-AAG activity was observed although early study termination meant study endpoints were not reached. Stable disease rates can be incorporated into trials screening for anti-melanoma activity and further study of HSP90 inhibitors in melanoma should be considered..
Fisher, R.
Cahalin, P.
Gore, M.
Larkin, J.
(2012). A tale of two tumours and a plea for progress. Lancet oncol,
Vol.13
(2),
pp. 124-125.
Turajlic, S.
Furney, S.J.
Lambros, M.B.
Mitsopoulos, C.
Kozarewa, I.
Geyer, F.C.
Mackay, A.
Hakas, J.
Zvelebil, M.
Lord, C.J.
Ashworth, A.
Thomas, M.
Stamp, G.
Larkin, J.
Reis-Filho, J.S.
Marais, R.
(2012). Whole genome sequencing of matched primary and metastatic acral melanomas. Genome res,
Vol.22
(2),
pp. 196-207.
show abstract
Next generation sequencing has enabled systematic discovery of mutational spectra in cancer samples. Here, we used whole genome sequencing to characterize somatic mutations and structural variation in a primary acral melanoma and its lymph node metastasis. Our data show that the somatic mutational rates in this acral melanoma sample pair were more comparable to the rates reported in cancer genomes not associated with mutagenic exposure than in the genome of a melanoma cell line or the transcriptome of melanoma short-term cultures. Despite the perception that acral skin is sun-protected, the dominant mutational signature in these samples is compatible with damage due to ultraviolet light exposure. A nonsense mutation in ERCC5 discovered in both the primary and metastatic tumors could also have contributed to the mutational signature through accumulation of unrepaired dipyrimidine lesions. However, evidence of transcription-coupled repair was suggested by the lower mutational rate in the transcribed regions and expressed genes. The primary and the metastasis are highly similar at the level of global gene copy number alterations, loss of heterozygosity and single nucleotide variation (SNV). Furthermore, the majority of the SNVs in the primary tumor were propagated in the metastasis and one nonsynonymous coding SNV and one splice site mutation appeared to arise de novo in the metastatic lesion..
Gruenwald, V.
Karakiewicz, P.I.
Bavbek, S.E.
Miller, K.
Machiels, J.-.
Lee, S.-.
Larkin, J.
Bono, P.
Rha, S.Y.
Castellano, D.
Blank, C.U.
Knox, J.J.
Hawkins, R.
Anak, O.
Rosamilia, M.
Booth, J.
Pirotta, N.
Bodrogi, I.
Grp, R.E.
(2012). An international expanded-access programme of everolimus: Addressing safety and efficacy in patients with metastatic renal cell carcinoma who progress after initial vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapy. European journal of cancer,
Vol.48
(3),
pp. 324-332.
Fisher, R.
Larkin, J.
(2012). Treatment of brain metastases in patients with melanoma. Lancet oncol,
Vol.13
(5),
pp. 434-435.
Young, K.
Minchom, A.
Larkin, J.
(2012). BRIM-1, -2 and -3 trials: improved survival with vemurafenib in metastatic melanoma patients with a BRAF(V600E) mutation. Future oncol,
Vol.8
(5),
pp. 499-507.
show abstract
Following Phase I and II studies revealing vemurafenib to be a safe potent inhibitor of mutated BRAF in patients with metastatic melanoma, a multicenter randomized Phase III trial was carried out to compare vemurafenib with dacarbazine in treatment-naive patients. The interim analysis results from this trial, BRIM-3, were sufficient for an independent data and safety monitoring board to recommend crossover from dacarbazine to vemurafenib, vemurafenib being associated with a relative risk reduction of 63% in the risk of death and 74% in the risk of death or disease progression compared with dacarbazine (p < 0.001 for both comparisons) with an acceptable toxicity profile. Such striking results have prompted analysis of our approach to the classification and treatment of metastatic melanoma in an age of molecular markers and targeted therapy..
Gerlinger, M.
Santos, C.R.
Spencer-Dene, B.
Martinez, P.
Endesfelder, D.
Burrell, R.A.
Vetter, M.
Jiang, M.
Saunders, R.E.
Kelly, G.
Dykema, K.
Rioux-Leclercq, N.
Stamp, G.
Patard, J.J.
Larkin, J.
Howell, M.
Swanton, C.
(2012). Genome-wide RNA interference analysis of renal carcinoma survival regulators identifies MCT4 as a Warburg effect metabolic target. J pathol,
Vol.227
(2),
pp. 146-156.
show abstract
Clear cell renal cell carcinoma (ccRCC) is the most common pathological subtype of kidney cancer. Here, we integrated an unbiased genome-wide RNA interference screen for ccRCC survival regulators with an analysis of recurrently overexpressed genes in ccRCC to identify new therapeutic targets in this disease. One of the most potent survival regulators, the monocarboxylate transporter MCT4 (SLC16A3), impaired ccRCC viability in all eight ccRCC lines tested and was the seventh most overexpressed gene in a meta-analysis of five ccRCC expression datasets. MCT4 silencing impaired secretion of lactate generated through glycolysis and induced cell cycle arrest and apoptosis. Silencing MCT4 resulted in intracellular acidosis, and reduction in intracellular ATP production together with partial reversion of the Warburg effect in ccRCC cell lines. Intra-tumoural heterogeneity in the intensity of MCT4 protein expression was observed in primary ccRCCs. MCT4 protein expression analysis based on the highest intensity of expression in primary ccRCCs was associated with poorer relapse-free survival, whereas modal intensity correlated with Fuhrman nuclear grade. Consistent with the potential selection of subclones enriched for MCT4 expression during disease progression, MCT4 expression was greater at sites of metastatic disease. These data suggest that MCT4 may serve as a novel metabolic target to reverse the Warburg effect and limit disease progression in ccRCC..
Larkin, J.
Esser, N.
Calvo, E.
Tsuchihashi, Z.
Fiedler, U.
Graeser, R.
Kim, D.
(2012). Efficacy of sequential treatment with sunitinib-everolimus in an orthotopic mouse model of renal cell carcinoma. Anticancer res,
Vol.32
(7),
pp. 2399-2406.
show abstract
BACKGROUND/AIM: Sequential treatment with targeted agents is standard of care for patients with metastatic renal cell carcinoma (mRCC). However, clinical data directly comparing treatment outcomes with a mammalian target of rapamycin inhibitor or a vascular endothelial growth factor-targeted agent in the second-line setting are lacking. We evaluated sequential treatment in a syngeneic, orthotopic mouse model of mRCC. MATERIALS AND METHODS: BALB/c mice were orthotopically implanted with murine RCC (RENCA) cells expressing luciferase and randomized to vehicle, sunitinib, sunitinib followed by sorafenib, or sunitinib followed by everolimus. Tumor growth and metastases were assessed by in vivo (whole body) and ex vivo (primary tumor, lung, liver) luciferase activity and necropsies, performed on day 20 or 46 for vehicle and treatment groups, respectively. RESULTS: Sunitinib followed by everolimus was associated with reduced luciferase activity and primary tumor weight and volume compared with sunitinib, and sunitinib followed by sorafenib. CONCLUSION: Sequential therapy with sunitinib followed by everolimus demonstrated significant antitumor and anti-metastatic effects..
Gerlinger, M.
Rowan, A.J.
Horswell, S.
Math, M.
Larkin, J.
Endesfelder, D.
Gronroos, E.
Martinez, P.
Matthews, N.
Stewart, A.
Tarpey, P.
Varela, I.
Phillimore, B.
Begum, S.
McDonald, N.Q.
Butler, A.
Jones, D.
Raine, K.
Latimer, C.
Santos, C.R.
Nohadani, M.
Eklund, A.C.
Spencer-Dene, B.
Clark, G.
Pickering, L.
Stamp, G.
Gore, M.
Szallasi, Z.
Downward, J.
Futreal, P.A.
Swanton, C.
(2012). Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N engl j med,
Vol.366
(10),
pp. 883-892.
show abstract
BACKGROUND: Intratumor heterogeneity may foster tumor evolution and adaptation and hinder personalized-medicine strategies that depend on results from single tumor-biopsy samples. METHODS: To examine intratumor heterogeneity, we performed exome sequencing, chromosome aberration analysis, and ploidy profiling on multiple spatially separated samples obtained from primary renal carcinomas and associated metastatic sites. We characterized the consequences of intratumor heterogeneity using immunohistochemical analysis, mutation functional analysis, and profiling of messenger RNA expression. RESULTS: Phylogenetic reconstruction revealed branched evolutionary tumor growth, with 63 to 69% of all somatic mutations not detectable across every tumor region. Intratumor heterogeneity was observed for a mutation within an autoinhibitory domain of the mammalian target of rapamycin (mTOR) kinase, correlating with S6 and 4EBP phosphorylation in vivo and constitutive activation of mTOR kinase activity in vitro. Mutational intratumor heterogeneity was seen for multiple tumor-suppressor genes converging on loss of function; SETD2, PTEN, and KDM5C underwent multiple distinct and spatially separated inactivating mutations within a single tumor, suggesting convergent phenotypic evolution. Gene-expression signatures of good and poor prognosis were detected in different regions of the same tumor. Allelic composition and ploidy profiling analysis revealed extensive intratumor heterogeneity, with 26 of 30 tumor samples from four tumors harboring divergent allelic-imbalance profiles and with ploidy heterogeneity in two of four tumors. CONCLUSIONS: Intratumor heterogeneity can lead to underestimation of the tumor genomics landscape portrayed from single tumor-biopsy samples and may present major challenges to personalized-medicine and biomarker development. Intratumor heterogeneity, associated with heterogeneous protein function, may foster tumor adaptation and therapeutic failure through Darwinian selection. (Funded by the Medical Research Council and others.)..
Khattak, M.
Gore, M.
Larkin, J.
Strauss, D.
Thomas, M.
Hayes, A.
Harrington, K.
(2012). Adjuvant nodal irradiation in melanoma. Lancet oncol,
Vol.13
(8),
pp. e326-e327.
Larkin, J.M.
Fisher, R.A.
Gore, M.E.
(2012). Adjuvant Interferon Therapy for Patients at High Risk for Recurrent Melanoma: An Updated Systematic Review. Clinical oncology,
Vol.24
(6),
pp. 410-412.
Thway, K.
du Parcq, J.
Larkin, J.M.
Fisher, C.
Livni, N.
(2012). Metastatic renal mucinous tubular and spindle cell carcinoma Atypical behavior of a rare, morphologically bland tumor. Ann diagn pathol,
Vol.16
(5),
pp. 407-410.
show abstract
Mucinous tubular and spindle cell carcinoma (MTSCC) is a rare, distinctive renal neoplasm characterized by an admixture of cuboidal cells in tubules and sheets of spindle cells, typically with low-grade nuclei and a myxoid or mucinous background. It is characteristically of low malignant potential, and only rare metastatic cases have been reported. We describe a case in which the patient presented with extensive regional and distant metastases, but both primary and metastatic tumor showed the typical histomorphology of bland cuboidal or spindle cells lacking pleomorphism, mitoses, and necrosis. Almost all previous cases of metastatic MTSCCs have shown nuclear atypia or sarcomatoid morphology of the primary tumor; and metastatic renal MTSCC in which the primary neoplasm does not display atypical features is exceptional, serving to highlight that these rare tumors can behave aggressively even with "indolent" histological appearances..
Larkin, J.M.
Blank, C.U.
Bono, P.
Gogov, S.
Panneerselvam, A.
Garay, C.A.
Grünwald, V.
REACT Study Group,
(2012). Everolimus in patients with metastatic renal cell carcinoma refractory to VEGF-targeted therapy: REACT subgroup analysis of prior therapy. J clin oncol,
Vol.30
(5_suppl),
p. 391.
show abstract
391 Background: Efficacy of everolimus (EVE) in metastatic renal cell carcinoma (mRCC) refractory to vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFR-TKI) therapy is well established. The REACT (RAD001 Expanded Access Clinical Trial in RCC) study was initiated to provide patients with VEGFR-TKI-refractory mRCC access to EVE in advance of regulatory approval. METHODS: REACT, an open-label, international, expanded-access clinical trial (Clinicaltrials.gov: NCT00655252 ) enrolled patients with measurable or nonmeasurable mRCC of any histology who were intolerant of, or progressed while on, VEGFR-TKI therapy. Long-term safety of EVE 10 mg/day in patients with mRCC, as determined by overall incidence of grade 3/4 and serious adverse events (AEs) was documented. RECIST-defined tumor response was also assessed by local investigator. Subgroup analyses evaluated effect of prior treatment on safety and efficacy of EVE. RESULTS: Of 1367 patients enrolled, most (92.7%) had progressed on prior VEGFR-TKI therapy, and some (24.4%) were VEGFR-TKI intolerant. Across patient subgroups by prior VEGFR-TKI treatment, median EVE treatment duration was similar (Table). Best overall response rates were similar in the VEGFR-TKI-intolerant subgroup and overall populations: respectively, 1.8% and 1.7% had partial response (PR) while 53.5% and 51.6% had stable disease (SD). Incidence of grade 3/4 AEs across all prior treatment subgroups were similar to those of the overall population. (See table.) Conclusions: Patients enrolled in REACT derived benefit from EVE irrespective of prior VEGFR-TKI therapy, including VEGFR-TKI-intolerant patients. EVE is well tolerated and affords disease stabilization in the majority of patients with VEGFR-TKI-refractory mRCC, and is the standard of care in this patient population. [Table: see text]..
Blank, C.U.
Bono, P.
Larkin, J.M.
Gogov, S.
Panneerselvam, A.
Garay, C.A.
Grünwald, V.
REACT Study Group,
(2012). Safety and efficacy of everolimus in patients with non-clear cell renal cell carcinoma refractory to VEGF-targeted therapy: Subgroup analysis of REACT. J clin oncol,
Vol.30
(5_suppl),
p. 402.
show abstract
402 Background: Metastatic non-clear cell renal cell carcinoma (mncRCC), which accounts for about 25% of all RCCs, is characterized by resistance to treatment and poor overall survival. Despite recent advances in targeted therapies for patients with mRCC, effective therapies for patients with mncRCC remain limited. The REACT (RAD001 Expanded Access Clinical Trial in RCC) study was initiated to provide patients with mRCC of any histology refractory to VEGF-targeted therapy access to everolimus in advance of regulatory approval. METHODS: REACT, an open-label, international, expanded-access program (Clinicaltrials.gov: NCT00655252 ) enrolled patients with measurable or nonmeasurable mRCC of any histology who were intolerant of, or progressed while on, VEGFR-TKI therapy in order to evaluate the long-term safety of everolimus 10 mg daily. Overall incidence of grade 3/4 and serious adverse events (AEs) were recorded, as was tumor response to everolimus according to RECIST criteria. A subgroup analysis of safety and efficacy in patients with mncRCC was performed. RESULTS: Of 1367 patients enrolled, 75 patients (5.5%) had mncRCC. Median everolimus treatment duration in the mncRCC subgroup was 12.14 weeks (range, 0.9-49.0 weeks) and in the overall REACT population it was 14.0 weeks (range, 0.1-83.7 weeks). In the mncRCC subgroup, most commonly reported grade 3/4 AEs were anemia (17.3%), dyspnea (10.7%), pleural effusion (9.3%), fatigue (8.0%), and hyperglycemia (6.6%). Best overall response was similar in the mncRCC subgroup and overall population: respectively, 1.3% and 1.7% had partial response and 49.3% and 51.6% had stable disease. CONCLUSIONS: Although patients with mncRCC had a slightly lower treatment duration than the overall REACT population, approximately 50% of these patients achieved disease control on treatment. In this subgroup, everolimus was well tolerated, no new safety issues were observed, and the AE profile was consistent with that of the overall population. These encouraging results of the safety and efficacy of everolimus in patients with mncRCC support further evaluation of everolimus in these patients..
Larkin, J.M.
Blank, C.U.
Bono, P.
Gogov, S.
Panneerselvam, A.
Garay, C.A.
Gruenwald, V.
Grp, R.E.
(2012). Everolimus in patients with metastatic renal cell carcinoma refractory to VEGF-targeted therapy: REACT subgroup analysis of prior therapy. Journal of clinical oncology,
Vol.30
(5).
Blank, C.U.
Bono, P.
Larkin, J.M.
Gogov, S.
Panneerselvam, A.
Garay, C.A.
Gruenwald, V.
Grp, R.E.
(2012). Safety and efficacy of everolimus in patients with non-clear cell renal cell carcinoma refractory to VEGF-targeted therapy: Subgroup analysis of REACT. Journal of clinical oncology,
Vol.30
(5).
Khattak, M.A.
Fisher, R.A.
Pickering, L.M.
Gore, M.E.
Larkin, J.M.
(2012). Endobronchial metastases from renal cell carcinoma: a late manifestation of the disease with an increasing incidence. Bju int,
Vol.110
(10),
pp. 1407-1408.
Sinha, R.
Edmonds, K.
Newton-Bishop, J.A.
Gore, M.E.
Larkin, J.
Fearfield, L.
(2012). Cutaneous adverse events associated with vemurafenib in patients with metastatic melanoma: practical advice on diagnosis, prevention and management of the main treatment-related skin toxicities. Br j dermatol,
Vol.167
(5),
pp. 987-994.
show abstract
Until recently, no effective treatment was available for patients with metastatic malignant melanoma, and median overall survival was little more than 6 months with the current standard of care, dacarbazine. In 2012, the first specific BRAF mutation inhibitor, vemurafenib, was licensed for the monotherapy of adults with BRAF V600 mutation-positive unresectable or metastatic melanoma. Like other targeted therapies, vemurafenib is associated with a predictable pattern of adverse events, including skin toxicities. We review the most common cutaneous adverse events associated with vemurafenib, based on data from clinical trials, and our own experiences of treating patients in trials and clinical practice. Overall, these toxicities are not preventable, but they rarely necessitate permanent treatment discontinuation and are generally manageable with dose modification and supportive care. We provide a treatment algorithm offering guidance on the most appropriate approach to managing the main skin toxicities to help clinicians unfamiliar with this novel agent to become confident in using vemurafenib effectively in the management of patients with metastatic melanoma..
Proskorovsky, I.
Benedict, A.
Larkin, J.M.
Sandin, R.
Chen, C.
(2012). AXITINIB (AXI) AND BEST SUPPORTIVE CARE (BSC) IN THE TREATMENT OF SUNITINIB-REFRACTORY PATIENTS WITH METASTATIC RENAL CELL CARCINOMA (MRCC): RESULTS OF A SIMULATED TREATMENT COMPARISON (STC) ANALYSES. Value in health,
Vol.15
(7),
pp. A410-A410.
Flaherty, K.T.
Robert, C.
Hersey, P.
Nathan, P.
Garbe, C.
Milhem, M.
Demidov, L.V.
Hassel, J.C.
Rutkowski, P.
Mohr, P.
Dummer, R.
Trefzer, U.
Larkin, J.M.
Utikal, J.
Dreno, B.
Nyakas, M.
Middleton, M.R.
Becker, J.C.
Casey, M.
Sherman, L.J.
Wu, F.S.
Ouellet, D.
Martin, A.-.
Patel, K.
Schadendorf, D.
Grp, M.E.
(2012). Improved Survival with MEK Inhibition in BRAF-Mutated Melanoma. New england journal of medicine,
Vol.367
(2),
pp. 107-114.
Gerlinger, M.
Rowan, A.
Horswell, S.
Larkin, J.
Endesfelder, D.
Gronroos, E.
Martinez, P.
Matthews, N.
Stewart, A.
Tarpey, P.
Varela, I.
Phillimore, B.
Begum, S.
McDonald, N.
Butler, A.
Jones, D.
Raine, K.
Latimer, C.
Santos, C.
Nohadani, M.
Eklund, A.
Spencer-Dene, B.
Clark, G.
Pickering, L.
Stamp, G.
Gore, M.
Szallasi, Z.
Downward, J.
Futreal, P.A.
Swanton, C.
(2012). Abstract 964: Intra-tumor heterogeneity and Darwinian selection revealed by multi-region exome sequencing of renal cell carcinomas. Cancer research,
Vol.72
(8_Supplement),
pp. 964-964.
show abstract
Abstract
Background: Genetic intra-tumor heterogeneity (ITH) may foster tumor adaptation by providing selectable phenotypes for Darwinian evolution. Extensive genetic heterogeneity may also hinder personalized medicine strategies that rely on the portrayal of the mutational landscape from single tumor biopsies. Methods: To examine ITH, we have subjected multiple biopsies from primary renal cell carcinomas and associated metastatic sites to exome capture sequencing (n=2), SNP-array based chromosomal aberration and ploidy profiling analysis (n=4). Phylogenetic relationships of tumor regions were reconstructed by clonal ordering of non-synonymous somatic mutations. The phenotypic consequences of genetic ITH were characterised by immunohistochemistry, mutation functional analysis and mRNA expression profiling. Results: Phylogenetic reconstruction revealed branched evolutionary tumor growth with 63-69% of somatic mutations identified from single biopsies not detectable across all sequenced tumor regions. Independent tumor suppressor gene loss of function mutations with distinct regional distributions were detected within individual tumors: SETD2 harbored 5 different mutations in 2 tumors and PTEN and KDM5C two different mutations in one tumor, each. Thus, despite genetic divergence during tumor progression, phenotypic convergent evolution occurred, indicating a high degree of early mutational diversity. ITH was observed for a mutation in the kinase domain of mTOR, correlating with S6 and 4EBP phosphorylation specifically in cancer regions carrying the mutation and constitutive activation of mTOR kinase activity in vitro. Expression of a renal cancer-specific prognostic signature differed between tumor regions. Chromosomal aberration analysis revealed extensive ITH with 26/30 tumor biopsies from four tumors harboring divergent allelic imbalance profiles. Ploidy profiling revealed heterogeneity in two out of four tumors and identified an aneuploid tumor cell population in a metastasis that probably evolved from a tetraploid intermediate detectable in the primary tumor. Conclusions: Genetic ITH was present in all tumors and occurs through spatially separated heterogeneous somatic mutations and chromosomal and ploidy aberrations leading to both, phenotypic intra-tumor diversity (mTOR activating mutation) and convergent loss of function(SETD2, PTEN and KDM5C). ITH can lead to underestimation of the tumor genomic landscape portrayed from single biopsies and may present significant challenges to personalized medicine and biomarker development. ITH, associated with heterogeneous protein function, may foster tumor adaptation and therapeutic failure through Darwinian selection. Targeting mutations commonly located on the trunks, rather than the branches of phylogenetic trees, may improve therapeutic outcomes.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 964. doi:1538-7445.AM2012-964.
Kirkwood, J.M.
Bastholt, L.
Robert, C.
Sosman, J.
Larkin, J.
Hersey, P.
Middleton, M.
Cantarini, M.
Zazulina, V.
Kemsley, K.
Dummer, R.
(2012). Phase II, Open-Label, Randomized Trial of the MEK1/2 Inhibitor Selumetinib as Monotherapy versus Temozolomide in Patients with Advanced Melanoma. Clinical cancer research,
Vol.18
(2),
pp. 555-567.
Larkin, J.
Goh, X.Y.
Vetter, M.
Pickering, L.
Swanton, C.
(2012). Epigenetic regulation in RCC: opportunities for therapeutic intervention?. Nat rev urol,
Vol.9
(3),
pp. 147-155.
show abstract
Renal cell carcinoma (RCC) is a constellation of malignancies of different histological subtypes arising from the renal parenchyma. The clear cell histological subtype (ccRCC) accounts for around 75% of RCCs and is characterized by distinct genetic abnormalities, of which the loss of function of the von Hippel-Lindau (VHL) tumor suppressor gene is the most common. Inactivation of other tumor suppressor genes such as SETD2, KDM6A, KDM5C and PBRM1 has been reported in ccRCC--notably, the proteins encoded by these genes are involved in histone and chromatin regulation. Furthermore, the PBRM1 and SETD2 genes are located on the short arm of chromosome 3 near the VHL locus. Chromatin and histones modify gene expression and, as a consequence, their function is tightly regulated. Data from RNA interference (RNAi) assays suggest that loss of function of PBRM1 drives proliferation and growth of ccRCC, but the clinical relevance of this is unclear and restoring the function of these genes for therapeutic purposes is likely to be challenging. An improved understanding of histone and chromatin regulation in RCC biology and the consequences of intratumor heterogeneity might identify novel targets in RCC and present alternative therapeutic opportunities..
Swanton, C.
Larkin, J.
Gerlinger, M.
(2012). Intratumor Heterogeneity and Branched Evolution REPLY. New england journal of medicine,
Vol.366
(22),
pp. 2133-2133.
Fisher, R.
Pender, A.
Thillai, K.
Chowdhury, S.
Pickering, L.
Khabra, K.
Gore, M.
Larkin, J.
(2012). Observation as a treatment strategy for advanced renal cell carcinoma-a call for prospective validation. Front oncol,
Vol.2,
p. 155.
Fisher, R.
Larkin, J.
(2012). Vemurafenib: a new treatment for BRAF-V600 mutated advanced melanoma. Cancer manag res,
Vol.4,
pp. 243-252.
show abstract
The BRAF inhibitor, vemurafenib, has demonstrated improved progression-free and overall survival compared with chemotherapy in a randomized trial, and represents a new standard of care in patients with advanced melanoma harboring a BRAF-V600 mutation. A BRAF-V600 mutation is identified in approximately half of patients with cutaneous melanoma, and is unequivocally a biomarker predictive of profound clinical benefit for these patients. However, acquired vemurafenib resistance is a major clinical challenge and therapy is not yet curative. A substantial body of translational research has been performed alongside clinical trials of vemurafenib, providing key insights into the molecular basis of response and resistance. This review summarizes the development of vemurafenib for the treatment of BRAF-V600 mutant melanoma and discusses how knowledge of critical signaling pathways will be applied for its optimal clinical use in future..
Fisher, R.
Larkin, J.
Swanton, C.
(2012). Inter and intratumour heterogeneity: a barrier to individualized medical therapy in renal cell carcinoma?. Front oncol,
Vol.2,
p. 49.
Suwaki, N.
Vanhecke, E.
Atkins, K.M.
Graf, M.
Swabey, K.
Huang, P.
Schraml, P.
Moch, H.
Cassidy, A.M.
Brewer, D.
Al-Lazikani, B.
Workman, P.
De-Bono, J.
Kaye, S.B.
Larkin, J.
Gore, M.E.
Sawyers, C.L.
Nelson, P.
Beer, T.M.
Geng, H.
Gao, L.
Qian, D.Z.
Alumkal, J.J.
Thomas, G.
Thomas, G.V.
(2011). A HIF-regulated VHL-PTP1B-Src signaling axis identifies a therapeutic target in renal cell carcinoma. Sci transl med,
Vol.3
(85),
p. 85ra47.
show abstract
Metastatic renal cell carcinoma (RCC) is a molecularly heterogeneous disease that is intrinsically resistant to chemotherapy and radiotherapy. Although therapies targeted to the molecules vascular endothelial growth factor and mammalian target of rapamycin have shown clinical effectiveness, their effects are variable and short-lived, underscoring the need for improved treatment strategies for RCC. Here, we used quantitative phosphoproteomics and immunohistochemical profiling of 346 RCC specimens and determined that Src kinase signaling is elevated in RCC cells that retain wild-type von Hippel-Lindau (VHL) protein expression. RCC cell lines and xenografts with wild-type VHL exhibited sensitivity to the Src inhibitor dasatinib, in contrast to cell lines that lacked the VHL protein, which were resistant. Forced expression of hypoxia-inducible factor (HIF) in RCC cells with wild-type VHL diminished Src signaling output by repressing transcription of the Src activator protein tyrosine phosphatase 1B (PTP1B), conferring resistance to dasatinib. Our results suggest that a HIF-regulated VHL-PTP1B-Src signaling pathway determines the sensitivity of RCC to Src inhibitors and that stratification of RCC patients with antibody-based profiling may identify patients likely to respond to Src inhibitors in RCC clinical trials..
Gore, M.E.
Larkin, J.M.
(2011). Challenges and opportunities for converting renal cell carcinoma into a chronic disease with targeted therapies. British journal of cancer,
Vol.104
(3),
pp. 399-406.
Khan, O.A.
Gore, M.
Lorigan, P.
Stone, J.
Greystoke, A.
Burke, W.
Carmichael, J.
Watson, A.J.
McGown, G.
Thorncroft, M.
Margison, G.P.
Califano, R.
Larkin, J.
Wellman, S.
Middleton, M.R.
(2011). A phase I study of the safety and tolerability of olaparib (AZD2281, KU0059436) and dacarbazine in patients with advanced solid tumours. British journal of cancer,
Vol.104
(5),
pp. 750-755.
Okera, M.
Chan, S.
Dernede, U.
Larkin, J.
Popat, S.
Gilbert, D.
Jones, L.
Osuji, N.
Sykes, H.
Oakley, C.
Pickering, L.
Lofts, F.
Chowdhury, S.
(2011). A prospective study of chemotherapy-induced febrile neutropenia in the South West London Cancer Network Interpretation of study results in light of NCAG/NCEPOD findings. British journal of cancer,
Vol.104
(3),
pp. 407-412.
Larkin, J.
Swanton, C.
Pickering, L.
(2011). Optimizing treatment of metastatic renal cell carcinoma by changing mechanism of action. Expert rev anticancer ther,
Vol.11
(4),
pp. 639-649.
show abstract
Novel targeted agents, such as VEGF receptor-tyrosine kinase inhibitors (VEGFR-TKIs) and mTOR inhibitors, have improved therapy for metastatic renal cell carcinoma. Sequential administration of agents with similar mechanisms of action has shown some efficacy in small retrospective studies; however, prospective Phase II studies have reached differing conclusions, and there is a current lack of prospective randomized data to validate this approach. Sequential administration of agents with different mechanisms of action has shown clinical efficacy in prospective trials, including a randomized Phase III study (RECORD-1) of the mTOR inhibitor everolimus, the only targeted agent recommended for use after VEGFR-TKI failure in metastatic renal cell carcinoma. Ongoing research will further define the relative merits of other sequences in terms of clinical outcome..
Bex, A.
Larkin, J.
Blank, C.
(2011). Non-Clear Cell Renal Cell Carcinoma: How New Biological Insight May Lead to New Therapeutic Modalities. Current oncology reports,
Vol.13
(3),
pp. 240-248.
Fisher, R.
Pickering, L.
Larkin, J.
(2011). New targeted therapies for renal cell carcinoma. Expert opin investig drugs,
Vol.20
(7),
pp. 933-945.
show abstract
INTRODUCTION: The aim of treatment in metastatic renal cell carcinoma is palliation. In the last 5 years, multiple targeted agents have been developed which have resulted in prolongation of patients' lives, but complete responses remain rare. New therapies and approaches are required to further improve the prognosis for patients with this disease. AREAS COVERED: This review discusses the molecular targets in renal cell carcinoma relevant to the development of new treatments and describes the progress of novel therapies. The evidence is compiled from the PubMed database and proceedings of scientific meetings, searched up to December 2010. EXPERT OPINION: A multitude of experimental agents are in clinical development and offer theoretical advantages over those currently in use. It is hoped that these treatments will result in better long-term control of metastatic renal cell carcinoma, with improved side effect profiles, but curative treatment in this disease remains elusive until the mechanisms underlying response and resistance to therapy are elucidated. Progress in the field has been limited by inadequate tissue collection within clinical trials; current and future clinical trial design will incorporate a larger translational component in an attempt to establish predictive biomarkers..
Josephs, D.
Hutson, T.E.
Cowey, C.L.
Pickering, L.M.
Larkin, J.M.
Gore, M.E.
Van Hemelrijck, M.
McDermott, D.F.
Powles, T.
Chowdhury, P.
Karapetis, C.
Harper, P.G.
Choueiri, T.K.
Chowdhury, S.
(2011). Efficacy and toxicity of sunitinib in patients with metastatic renal cell carcinoma with severe renal impairment or on haemodialysis. Bju international,
Vol.108
(8),
pp. 1279-1283.
Larkin, J.M.
Gore, M.E.
(2011). Primary Excision Margins and Sentinel Lymph Node Biopsy in Clinically Node-negative Melanoma of the Trunk or Extremities. Clinical oncology,
Vol.23
(9),
pp. 569-571.
Minchom, A.
Young, K.
Larkin, J.
(2011). Ipilimumab: showing survival benefit in metastatic melanoma. Future oncol,
Vol.7
(11),
pp. 1255-1264.
show abstract
Ipilimumab is a fully humanized monoclonal antibody to cytotoxic T-lymphocyte-associated antigen 4. Data from preclinical and clinical studies have shown that ipilimumab can cause tumor regression in patients with metastatic melanoma with response rates of 5.8-22%. Phase III trials have demonstrated a benefit in median overall survival in the first-line setting in combination with dacarbazine versus dacarbazine alone (11.2 vs 9.1 months) and in the second-line setting in combination with gp100 versus gp100 alone (10.1 vs 6.4 months). The main toxicities of ipilimumab are immune related, most commonly skin and gastrointestinal. Bowel perforation and treatment-related deaths have occurred, although prompt use of steroids and other immunosuppressive agents can minimize this risk..
Sanz-Moreno, V.
Gaggioli, C.
Yeo, M.
Albrengues, J.
Wallberg, F.
Viros, A.
Hooper, S.
Mitter, R.
Féral, C.C.
Cook, M.
Larkin, J.
Marais, R.
Meneguzzi, G.
Sahai, E.
Marshall, C.J.
(2011). ROCK and JAK1 signaling cooperate to control actomyosin contractility in tumor cells and stroma. Cancer cell,
Vol.20
(2),
pp. 229-245.
show abstract
Proinflammatory cytokines are frequently observed in the tumor microenvironment, and chronic inflammation is involved in cancer initiation and progression. We show that cytokine signaling through the receptor subunit GP130-IL6ST and the kinase JAK1 generates actomyosin contractility through Rho-kinase dependent signaling. This pathway generates contractile force in stromal fibroblasts to remodel the extracellular matrix to create tracks for collective migration of squamous carcinoma cells and provides the high levels of actomyosin contractility required for migration of individual melanoma cells in the rounded, "amoeboid" mode. Thus, cytokine signaling can generate actomyosin contractility in both stroma and tumor cells. Strikingly, actomyosin contractility itself positively modulates activity of the transcription factor STAT3 downstream of JAK1, demonstrating positive feedback within the signaling network..
Larkin, J.M.
Fisher, R.A.
Pickering, L.M.
Sohaib, S.A.
Ghosn, M.
Christmas, T.
Cordiner, R.L.
Gore, M.E.
(2011). Chromophobe Renal Cell Carcinoma With Prolonged Response to Sequential Sunitinib and Everolimus. Journal of clinical oncology,
Vol.29
(9),
pp. E241-E242.
Ratnayake, G.
Pender, A.
Pickering, L.M.
Gore, M.E.
Larkin, J.M.
(2011). Intrapatient correlation of clinical benefit from VEGF and mTOR inhibition in metastatic renal cell carcinoma. Journal of clinical oncology,
Vol.29
(15).
Hutson, T.E.
Bukowski, R.M.
Rini, B.I.
Gore, M.E.
Larkin, J.M.
Figlin, R.A.
Barrios, C.H.
Escudier, B.
Lin, X.
Fly, K.D.
Martell, B.
Matczak, E.
Motzer, R.J.
(2011). A pooled analysis of the efficacy and safety of sunitinib in elderly patients (pts) with metastatic renal cell carcinoma (mRCC). Journal of clinical oncology,
Vol.29
(15).
Leary, A.
Pickering, L.M.
Larkin, J.M.
Leach, M.O.
Gore, M.E.
Sohaib, A.
Collins, D.J.
Koh, D.
(2011). Quantitative diffusion-weighted (DW) MR imaging of microcapillary perfusion and tissue diffusivity as biomarkers of response of renal cell carcinoma (RCC) to treatment with sunitinib. Journal of clinical oncology,
Vol.29
(15).
Fisher, R.A.
Pender, A.
Thillai, K.
Chowdhury, S.
Pickering, L.M.
Rose, S.S.
Gore, M.E.
Larkin, J.M.
(2011). Observation prior to systemic therapy in patients with metastatic renal cell carcinoma in the kinase inhibitor era. Journal of clinical oncology,
Vol.29
(15).
Chapman, P.B.
Hauschild, A.
Robert, C.
Larkin, J.M.
Haanen, J.B.
Ribas, A.
Hogg, D.
O'Day, S.
Ascierto, P.A.
Testori, A.
Lorigan, P.
Dummer, R.
Sosman, J.A.
Garbe, C.
Lee, R.J.
Nolop, K.B.
Nelson, B.
Hou, J.
Flaherty, K.T.
McArthur, G.A.
(2011). Phase III randomized, open-label, multicenter trial (BRIM3) comparing BRAF inhibitor vemurafenib with dacarbazine (DTIC) in patients with (V600E)BRAF-mutated melanoma. J clin oncol,
Vol.29
(18_suppl),
p. LBA4.
show abstract
LBA4 Background: About 50% of melanomas have an activating (V600E)BRAF mutation which led to the hypothesis that inhibition of the mutated BRAF kinase may be of clinical benefit. Phase I and II trials with vemurafenib (previously PLX4032/RO5185426), an orally available inhibitor of oncogenic BRAF kinase, showed response rates (RR; CR+PR) >50% in (V600E)BRAF- mutated melanoma patients (pts). We conducted a phase III trial to determine if vemurafenib improved overall survival (OS) and progression-free survival (PFS) in melanoma pts with (V600E)BRAF mutation. METHODS: Pts with previously untreated, unresectable stage IIIC or stage IV melanoma that tested positive for (V600E)BRAF mutation by the cobas 4800 BRAF V600 Mutation Test were randomized (1:1) to vemurafenib (960 mg po bid) or DTIC (1,000 mg/m(2), IV, q3w). Randomization was stratified by PS, stage, LDH, and geographic region. Pts were assessed for tumor responses after weeks 6, 12, and then q9 weeks. Co-primary endpoints were OS and PFS on the intent-to-treat population; secondary endpoints included RR, response duration, and safety. Final analysis was planned at 196 deaths. RESULTS: 675 pts were enrolled at 103 centers worldwide between Jan and Dec 2010. Treatment cohorts were well-balanced. At the pre-planned interim analysis (50% of deaths needed for final analysis), the hazard ratios for OS and PFS were 0.37 (95% CI 0.26 to 0.55; p<0.0001) and 0.26 (95% CI 0.20 to 0.33; p<0.0001), respectively, both in favor of vemurafenib. The confirmed RR was 48.4% and 5.5% to vemurafenib and DTIC, respectively, among the 65% of pts evaluable for RR to date. Benefit in OS, PFS, and RR was seen in all subgroups examined. Due to these data, the DTIC cohort has been allowed to cross over to vemurafenib. At the time of data analysis, 66% of vemurafenib pts and 25% DTIC pts were still on treatment. The most common toxicities of vemurafenib were: diarrhea, rash, alopecia, photosensitivity, fatigue, arthralgia, and keratoacanthoma/skin squamous cell carcinoma. CONCLUSIONS: Vemurafenib is associated with significantly improved OS and PFS compared to DTIC in pts with previously untreated, (V600E)BRAF-mutated metastatic melanoma..
Hutson, T.E.
Bukowski, R.M.
Rini, B.I.
Gore, M.E.
Larkin, J.M.
Figlin, R.A.
Barrios, C.H.
Escudier, B.
Lin, X.
Fly, K.D.
Martell, B.
Matczak, E.
Motzer, R.J.
(2011). A pooled analysis of the efficacy and safety of sunitinib in elderly patients (pts) with metastatic renal cell carcinoma (mRCC). J clin oncol,
Vol.29
(15_suppl),
p. 4604.
show abstract
4604 Background: Sunitinib is approved multinationally for mRCC treatment (Tx), with demonstrated activity and tolerability in both the first- and second-line Tx settings. Here, we report a retrospective analysis of the efficacy and safety of sunitinib as a function of age in pts with mRCC from 6 clinical trials. METHODS: Analyses included pooled data from 1,059 pts who received single-agent sunitinib on the approved 50 mg/d 4-week-on/2-week-off schedule (n=689; 65%) or at 37.5 mg continuous once-daily dosing (n=370; 35%), in both the first- (n=783; 74%) and second-line (n=276; 26%) Tx settings. Median progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier method and compared between pts <70 vs. ≥70 yrs of age by log-rank test. Adverse event (AE) rates were also compared. RESULTS: Of 1,059 pts, 857 (81%) were of age <70 yrs and 202 (19%) ≥70 yrs, with median ages of 57 and 73 yrs, respectively. 73% and 59% were male, but otherwise baseline characteristics were similar. Median PFS was similar in both groups (9.0 vs. 10.9 mo; HR, 0.85; 95% CI, 0.70-1.02; P=0.0830), as was median OS (23.3 vs. 23.7 mo; HR, 0.94; 95% CI, 0.76-1.15; P=0.5441). In addition, efficacy was similar by age regardless of Tx setting. In first-line pts <70 vs. ≥70 yrs, median PFS and OS were 9.9 mo (95% CI, 8.3-10.7) vs. 11.0 mo (95% CI, 9.0-14.7) and 23.5 mo (95% CI, 21.1-27.6) vs. 25.5 mo (95% CI, 21.6-38.4); in second-line pts, median PFS and OS were 8.1 mo (95% CI, 7.8-8.7) vs. 8.4 mo (95% CI, 6.3-14.2) and 20.1 mo (95% CI, 16.2-25.0) vs. 15.8 mo (95% CI, 13.7-23.9). Most Tx-emergent AEs occurred at similar rates in both age groups; however, some AEs were significantly less common in pts aged <70 vs. ≥70 yrs, including fatigue (59% vs. 69%), decreased appetite/weight (29% vs. 53%), cough (20% vs. 29%), peripheral edema (17% vs. 27%), anemia (17% vs. 25%), and thrombocytopenia (16% vs. 25%; all P<0.05). Hand-foot syndrome was more common in younger pts (32% vs. 24%; P<0.05). CONCLUSIONS: In pts with mRCC, the efficacy of sunitinib was comparable in the elderly population, deriving similar benefit as younger pts regardless of Tx setting. The AE profiles were also similar, although some AEs were more common in elderly pts..
Fisher, R.A.
Pender, A.
Thillai, K.
Chowdhury, S.
Pickering, L.M.
St Rose, S.
Gore, M.E.
Larkin, J.M.
(2011). Observation prior to systemic therapy in patients with metastatic renal cell carcinoma in the kinase inhibitor era. J clin oncol,
Vol.29
(15_suppl),
p. 4630.
show abstract
4630 Background: Patients with metastatic renal cell carcinoma (mRCC) are heterogenous, with significant variation in clinical course. The use of vascular endothelial growth factor receptor (VEGFR) and mammalian target of rapamycin (mTOR) kinase inhibitors has dramatically changed the prognosis for these patients. However, these treatments are non-curative, necessitating chronic therapy. There is a cohort of patients with indolent disease in whom the initiation of systemic therapy is often deferred. It is inferred that the planned deferment of systemic therapy does not negatively impact on clinical benefit, but there is a lack of published data in the 'kinase inhibitor era' to support this contention. METHODS: This was a retrospective study. Patients with mRCC treated with sunitinib who had a planned period of observation prior to the initiation of systemic therapy because of asymptomatic or slowly progressive disease were analysed. The primary objective was to determine the progression free survival (PFS) of patients on deferred first-line systemic therapy. RESULTS: Records of 251 patients treated with sunitinib between 2005 and 2010 were reviewed; 64 patients who met the criteria were identified. The median age at diagnosis was 56 years and 75% were male; 80% had clear cell mRCC. All patients but one had a favourable or intermediate prognosis (Heng). The median time from diagnosis of metastases to starting treatment was 14.7 months (95% CI 10.4-16.3) Initial systemic therapy was interferon for 28% of patients and sunitinib for 65% of patients. Interferon patients had a median PFS of 6.3 months (95% CI 3.3-9.9), and sunitinib patients had a median PFS of 4.3 months (95% CI 3.6-7.3). Patients who received a VEGFR kinase inhibitor as second-line therapy after interferon had a median PFS of 7 months (95% CI 4.3-12.5). The median overall survival for all patients was 35 months (95% CI 26-42.3). CONCLUSIONS: In this cohort of patients with indolent favourable or intermediate prognosis mRCC, systemic treatment was deferred by a median of over one year but the efficacy of delayed sunitinib treatment was less than expected. Further study is required to define the group of patients for whom delayed systemic therapy is optimal..
Larkin, J.M.
Turajlic, S.
Nathan, P.D.
Lorigan, P.
Stamp, G.
Gonzalez de Castro, D.
Martin, N.
Griffiths, J.
Edmonds, K.
Sarker, S.
James, M.G.
A'Hern, R.
Coombes, G.
Snowdon, C.
Bliss, J.M.
Gore, M.E.
Marais, R.
(2011). A phase II trial of nilotinib in the treatment of patients with KIT mutated advanced acral and mucosal melanoma (NICAM). J clin oncol,
Vol.29
(15_suppl),
p. TPS229.
show abstract
TPS229 Background: Recent studies have indicated that KIT mutations occur in approximately 20% of acral and mucosal melanomas (Curtin, al. 2006; Beadling, et al. 2008). Several case reports have shown that KIT mutated melanomas can respond to treatment with KIT inhibitors (Hodi et al. 2008; Lutzky et al. 2008; Quintas-Cardama et al. 2008; Handolias et al. 2010; Itoh, et al. 2010; Satzger et al. 2010; Terheyden et al. 2010; Woodman and Davies 2010) suggesting that such tumours critically depend on upregulated KIT signalling. Nilotinib, which potently inhibits the tyrosine kinase activity of BCR-ABL and KIT, has been evaluated in patients with advanced KIT mutated GIST and has shown clinical efficacy at well tolerated doses (Demetri et al. 2009; Montemurro et al. 2009; Schlemmer et al. 2010). METHODS: NICAM is a single arm 2-stage open label phase II study of nilotinib in KIT mutated advanced mucosal or acral melanoma. Patients with KIT mutations known to confer resistance to nilotinib are excluded. The primary objective in this feasibility study is to evaluate the efficacy of nilotinib in KIT mutated advanced mucosal and acral melanoma with a primary endpoint of progression free survival at 6 months. Secondary endpoints include response rate at 12 weeks; overall survival; toxicity of treatment; correlation between the response to nilotinib and KIT genotype, KIT gene copy number and KIT expression. In addition, the following will be explored: 1. Suppression of phosphorylation of KIT and downstream pathways on day 15 tumour biopsies; 2. Possible mechanisms of resistance by analysis of biopsies obtained at disease progression; 3. The use of circulating tumour DNA for non-invasive KIT mutational testing; 4. Genetic lesions that potentially cooperate with oncogenic KIT in melanoma (using Next Generation Sequencing). All patients are treated until disease progression or unacceptable toxicity. If 2 or more of the first 9 patients are progression free at 6 months, patient entry will continue into the second stage until a total of 24 patients have been recruited. To date, 45 patients have been registered and screened for KIT mutation and 5 patients have entered the study..
Leary, A.
Pickering, L.M.
Larkin, J.M.
Leach, M.O.
Gore, M.E.
Sohaib, A.
Collins, D.J.
Koh, D.
(2011). Quantitative diffusion-weighted (DW) MR imaging of microcapillary perfusion and tissue diffusivity as biomarkers of response of renal cell carcinoma (RCC) to treatment with sunitinib. J clin oncol,
Vol.29
(15_suppl),
p. TPS154.
show abstract
TPS154 Background: The anti-angiogenic tyrosine kinase inhibitor, sunitinib has been shown to significantly improve progression-free (PFS) and overall survival in RCC (Motzer 2009). However assessing response by conventional imaging is inadequate as sunitinib can alter perfusion and induce necrosis with no change in tumor size (Jaffe 2006). DW-MRI measures the motion of water molecules using the apparent diffusion coefficient (ADC) to quantify tissue diffusivity (D), an indirect measure of tissue density. ADC values are low in viable tumor and increase with treatment-induced apoptosis or necrosis (Theony 2010). In addition, DW-MRI obtained using low diffusion weightings can measure tissue perfusion (f) (Theony 2010; Koh 2006). Therefore DW-MRI may provide an early marker of response to sunitinib in RCC by detecting both changes in perfusion (anti-angiogenic effect) and changes in tissue diffusivity (necrosis). METHODS: This is a single arm prospective study. Main inclusion criteria are metastatic clear cell RCC, eligible for first-line sunitinib and target lesion >2.5cm assessable by functional MRI. 30 patients will be enrolled and undergo DW-MRI at baseline and after 7 and 28 days of sunitinib. Two baseline DW-MRI are performed 1 day apart to assess reproducibility. Objective response will be assessed on CT after 12 weeks by RECIST and pts followed up for PFS. The primary endpoint is to determine whether DW-MRI can identify responders versus non-responders to sunitinib in RCC. Secondary endpoints include investigating whether quantitative measurement of diffusion and perfusion (ADC, D, f) by DW-MRI correlates with objective tumor response and PFS. For DW-MRI, targeted acquisition measurements will be made using up to 10b-values, ranging between 0 and 1000s/mm(2). Unenhanced T1- and T2-, DCE-MR imaging sequences will also be performed. Paired baseline measurements will be used to compute measurement reproducibility. Absolute and % change in ADC, D and f at 7 and 28 days will be compared to baseline, and the limits of baseline reproducibility (Bland-Altman Statistics) used to define whether biomarker change is significant..
Ratnayake, G.
Pender, A.
Pickering, L.M.
Gore, M.E.
Larkin, J.M.
(2011). Intrapatient correlation of clinical benefit from VEGF and mTOR inhibition in metastatic renal cell carcinoma. J clin oncol,
Vol.29
(15_suppl),
p. e15175.
show abstract
e15175 Background: Sequential inhibition of vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) signalling is the standard systemic therapy paradigm for metastatic renal cell carcinoma (mRCC). We investigated whether clinical benefit for mRCC patients treated with VEGF inhibitors (VEGFi) predicted clinical benefit from mTOR inhibitors (mTORi) in individual patients. METHODS: Data were analysed for mRCC patients treated with VEGFi and mTORi in either sequence. Median time on treatment (TT) for VEGFi and mTORi were compared using the Mann-Whitney U test, and Kendall's tau to assess correlation of VEGFi and mTORi TT for each patient. For patients treated with >1 VEGFi, TT for the 1(st) VEGFi was analysed. Patients were divided into 4 groups: TT of mTORi and VEGFi <6 and >6 months duration, comparing duration between groups with a log rank test. Modified Motzer Scores (mMS) at time of 1(st) VEGFi/mTORi for these 4 groups were calculated as surrogate markers for tumour biology. RESULTS: Thirty five patients received both mTORi and VEGFi to disease progression, of whom only 2 received mTORi before VEGFi. Seven patients were female, and median age at start of 1(st) VEGFi/mTORi was 58.9 years. The median TT for VEGFi and mTORi were 5.4 months (95% CI 2.2-8.6) and 6.9 months (95% CI 2.5-11.3) respectively, and not significantly different. Kendall tau intrapatient correlation coefficient for TT on mTORi and VEGFi was 0.069 (p=0.56), suggesting no significant correlation. The mean mMS for patients with TT on mTORi <6 vs >6 months were 2.00 and 1.89 (median 2 and 2) respectively (p=0.79), and 2.11 and 1.18 (median 2 and 1) respectively (p=0.00092) for TT on VEGFi. CONCLUSIONS: In this small retrospective analysis, there was no significant correlation within patients between TT for mTORi and VEGFi. The significantly lower mMS for patients on VEGFi with a TT >6 months vs <6 months is consistent with previous analyses by Heng and colleagues. No such significant difference was seen with mTORi, implying mMS may not have the same prognostic value. These associations require further study..
Chapman, P.B.
Hauschild, A.
Robert, C.
Larkin, J.M.
Haanen, J.B.
Ribas, A.
Hogg, D.
O'Day, S.
Ascierto, P.A.
Testori, A.
Lorigan, P.
Dummer, R.
Sosman, J.A.
Garbe, C.
Lee, R.J.
Nolop, K.B.
Nelson, B.
Hou, J.
Flaherty, K.T.
McArthur, G.A.
(2011). Phase III randomized, open-label, multicenter trial (BRIM3) comparing BRAF inhibitor RG7204 with dacarbazine in patients with V600E BRAF-mutated melanomas. J clin oncol,
Vol.29
(15_suppl),
p. LBA4.
show abstract
LBA4 The full, final text of this abstract will be available in Part II of the 2011 Annual Meeting Proceedings, distributed onsite at the Meeting on June 4, 2011, and as a supplement to the June 20, 2011, issue of Journal of Clinical Oncology..
Grünwald, V.
Karakiewicz, P.I.
Bavbek, S.E.
Miller, K.
Machiels, J.H.
Lee, S.
Larkin, J.M.
Bono, P.
Rha, S.Y.
Castellano, D.E.
Blank, C.U.
Knox, J.J.
Hawkins, R.
Yuan, R.R.
Rosamilia, M.
Booth, J.L.
Bodrogi, I.
REACT Study Group,
(2011). Final results of the international, expanded-access program of everolimus in patients with advanced renal cell carcinoma who progress after prior vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy. J clin oncol,
Vol.29
(15_suppl),
p. 4601.
show abstract
4601 Background: The phase III RECORD-1 trial established everolimus as the only agent proven to benefit patients with metastatic renal cell carcinoma (mRCC) after failure of initial VEGFr-TKI therapy. Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, more than doubled median progression-free survival compared with placebo, from 1.9 months to 4.9 months. The REACT (RAD001 Expanded Access Clinical Trial in RCC) study was initiated in order to address an unmet medical need and provide everolimus in advance of regulatory approval and commercial availability to patients with mRCC after failure of initial VEGFr-TKI therapy. METHODS: REACT was an open-label, international, expanded-access clinical trial (Clinicaltrials.gov: NCT00655252 ). Eligible patients had measurable or nonmeasurable mRCC of any histology, were intolerant of, or progressed while on, VEGFr-TKI therapy, had a Karnofsky performance score ≥70%, and had adequate bone marrow, hepatic, and renal function. Patients received everolimus 10 mg/day orally, with dose and schedule modifications allowed for toxicity. The primary objective of REACT was to evaluate the long-term safety of everolimus in patients with mRCC, as determined by the overall incidence of grade 3/4 and serious adverse events (AEs). Tumor response to everolimus was also assessed according to RECIST. RESULTS: A total of 1367 patients from 34 countries were enrolled. Safety findings and tumor responses were consistent with those observed in RECORD-1. The most commonly reported grade 3/4 AEs were anemia (13.4%), fatigue (6.7%), and dyspnea (6.4%), and the most frequent serious AEs were dyspnea (5.0%), pneumonia (4.7%), and anemia (4.1%). Median dose intensity was 10.0 mg/day; relative dose intensity ranged from 0.90 to 1.10 in 68.9% of patients. CONCLUSIONS: REACT evaluated the safety and tolerability of everolimus in a broader patient population than the controlled trial RECORD-1. Everolimus was well tolerated, with no new safety issues identified and infrequent dose reductions/interruptions in the majority of patients..
Gruenwald, V.
Karakiewicz, P.I.
Bavbek, S.E.
Miller, K.
Machiels, J.H.
Lee, S.
Larkin, J.M.
Bono, P.
Rha, S.Y.
Castellano, D.E.
Blank, C.U.
Knox, J.J.
Hawkins, R.
Yuan, R.R.
Rosamilia, M.
Booth, J.L.
Bodrogi, I.
Grp, R.E.
(2011). Final results of the international, expanded-access program of everolimus in patients with advanced renal cell carcinoma who progress after prior vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy. Journal of clinical oncology,
Vol.29
(15).
Chapman, P.B.
Hauschild, A.
Robert, C.
Larkin, J.M.
Haanen, J.B.
Ribas, A.
Hogg, D.
O'Day, S.
Ascierto, P.A.
Testori, A.
Lorigan, P.
Dummer, R.
Sosman, J.A.
Garbe, C.
Lee, R.J.
Nolop, K.B.
Nelson, B.
Hou, J.
Flaherty, K.T.
McArthur, G.A.
(2011). Phase III randomized, open-label, multicenter trial (BRIM3) comparing BRAF inhibitor RG7204 with dacarbazine in patients with V600E BRAF-mutated melanomas. Journal of clinical oncology,
Vol.29
(15).
Chapman, P.B.
Hauschild, A.
Robert, C.
Larkin, J.M.
Haanen, J.B.
Ribas, A.
Hogg, D.
O'Day, S.
Ascierto, P.A.
Testori, A.
Lorigan, P.
Dummer, R.
Sosman, J.A.
Garbe, C.
Lee, R.J.
Nolop, K.B.
Nelson, B.
Hou, J.
Flaherty, K.T.
McArthur, G.A.
(2011). Phase III randomized, open-label, multicenter trial (BRIM3) comparing BRAF inhibitor vemurafenib with dacarbazine (DTIC) in patients with (V600E)BRAF-mutated melanoma. Journal of clinical oncology,
Vol.29
(18).
Chapman, P.B.
Hauschild, A.
Robert, C.
Haanen, J.B.
Ascierto, P.
Larkin, J.
Dummer, R.
Garbe, C.
Testori, A.
Maio, M.
Hogg, D.
Lorigan, P.
Lebbe, C.
Jouary, T.
Schadendorf, D.
Ribas, A.
O'Day, S.J.
Sosman, J.A.
Kirkwood, J.M.
Eggermont, A.M.
Dreno, B.
Nolop, K.
Li, J.
Nelson, B.
Hou, J.
Lee, R.J.
Flaherty, K.T.
McArthur, G.A.
Grp, B.S.
(2011). Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation. New england journal of medicine,
Vol.364
(26),
pp. 2507-2516.
Fisher, R.
Larkin, J.
(2011). Renal cell cancer: what can we learn from pre-operative studies?. Front oncol,
Vol.1,
p. 51.
Larkin, J.
Fisher, R.
Pickering, L.
Thway, K.
Livni, N.
Fisher, C.
Gore, M.
(2010). Metastatic Mucinous Tubular and Spindle Cell Carcinoma of the Kidney Responding to Sunitinib. Journal of clinical oncology,
Vol.28
(28),
pp. E539-2.
Rennalls, L.P.
Seidl, T.
Larkin, J.M.
Wellbrock, C.
Gore, M.E.
Eisen, T.
Bruno, L.
(2010). The melanocortin receptor agonist NDP-MSH impairs the allostimulatory function of dendritic cells. Immunology,
Vol.129
(4),
pp. 610-619.
Mukherji, D.
Larkin, J.
Pickering, L.
(2010). Sunitinib for metastatic renal cell carcinoma. Future oncology,
Vol.6
(9),
pp. 1377-1385.
Goldstein, R.
Pickering, L.
Larkin, J.
(2010). Does axitinib (AG-01376) have a future role in metastatic renal cell carcinoma and other malignancies?. Expert review of anticancer therapy,
Vol.10
(10),
pp. 1545-1557.
Larkin, J.M.
Ferguson, T.R.
Pickering, L.M.
Edmonds, K.
James, M.G.
Thomas, K.
Banerji, U.
Berns, B.
de Boer, C.
Gore, M.E.
(2010). A phase I/II trial of sorafenib and infliximab in advanced renal cell carcinoma. Br j cancer,
Vol.103
(8),
pp. 1149-1153.
show abstract
BACKGROUND: There is clinical evidence to suggest that tumour necrosis factor-α (TNF-α) may be a therapeutic target in renal cell carcinoma (RCC). Multi-targeted kinase inhibitors, such as sorafenib and sunitinib, have become standard of care in advanced RCC. The anti-TNF-α monoclonal antibody infliximab and sorafenib have differing cellular mechanisms of action. We conducted a phase I/II trial to determine the safety and efficacy of infliximab in combination with sorafenib in patients with advanced RCC. METHODS: Eligible patients were systemic treatment-naive or had received previous cytokine therapy only. Sorafenib and infliximab were administered according to standard schedules. The study had two phases: in phase I, the safety and toxicity of the combination of full-dose sorafenib and two dose levels of infliximab were evaluated in three and three patients, respectively, and in phase II, further safety, toxicity and efficacy data were collected in an expanded patient population. RESULTS: Acceptable safety was reported for the first three patients (infliximab 5 mg kg⁻¹) in phase 1. Sorafenib 400 mg twice daily and infliximab 10 mg kg⁻¹ were administered to a total of 13 patients (three in phase 1 and 10 in phase 2). Adverse events included grade 3 hand-foot syndrome (31%), rash (25%), fatigue (19%) and infection (19%). Although manageable, toxicity resulted in 75% of the patients requiring at least one dose reduction and 81% requiring at least one dose delay of sorafenib. Four patients were progression-free at 6 months (PFS₆ 31%); median PFS and overall survival were 6 and 14 months, respectively. CONCLUSION: Sorafenib and infliximab can be administered in combination, but a significant increase in the numbers of adverse events requiring dose adjustments of sorafenib was observed. There was no evidence of increased efficacy compared with sorafenib alone in advanced RCC. The combination of sorafenib and infliximab does not warrant further evaluation in patients with advanced RCC..
Pickering, L.M.
Constantinidou, A.
Larkin, J.M.
Sohaib, S.A.
Khatri, P.
Nathan, P.D.
Vinayan, A.
Ferguson, T.
St Rose, S.
Gore, M.E.
(2010). Sunitinib treatment for longer than 2 years for renal cell carcinoma. Journal of clinical oncology,
Vol.28
(15).
Larkin, J.M.
Hess, V.
Pickering, L.M.
Ferguson, T.
Forrest, R.
Gore, M.E.
(2010). Symptomatic brain metastases from renal cell carcinoma during treatment with sunitinib or sorafenib. Journal of clinical oncology,
Vol.28
(15).
Swanton, C.
Juul, N.
Larkin, J.M.
Eklund, A.
Li, Q.
Desmedt, C.
Sotiriou, C.
Pusztal, L.
Szallasi, Z.
(2010). Use of an RNA interference screen-derived mitotic and ceramide pathway metagene to predict response to paclitaxel combination chemotherapy in primary breast cancer. Journal of clinical oncology,
Vol.28
(15).
Larkin, J.
Gore, M.
(2010). Is advanced renal cell carcinoma becoming a chronic disease?. Lancet,
Vol.376
(9741),
pp. 574-575.
Fisher, R.A.
Larkin, J.
(2010). Malignant melanoma (metastatic). Bmj clin evid,
Vol.2010.
show abstract
INTRODUCTION: Each year in the UK there are 8100 new cases of malignant melanoma, and 1800 deaths, largely as a result of metastatic disease. The median survival of people with metastatic melanoma is 6 to 9 months after diagnosis, with 10% of people alive at 5 years. Chemotherapy is given with palliative rather than curative intent for metastatic disease. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of chemotherapy for metastatic melanoma? What are the effects of immunotherapy for metastatic melanoma? We searched: Medline, Embase, The Cochrane Library, and other important databases up to March 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 24 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: adding interferon alfa (with or without interleukin-2) to chemotherapy; dacarbazine; single-agent or combination chemotherapy; supportive palliative care alone or with chemotherapy; and temozolomide..
Larkin, J.M.
Pyle, L.M.
Gore, M.E.
(2010). Fatigue in renal cell carcinoma: the hidden burden of current targeted therapies. Oncologist,
Vol.15
(11),
pp. 1135-1146.
show abstract
Fatigue is one of the most common symptoms associated with cancer. Persistent fatigue can impair multiple aspects of daily functioning and quality of life, and patients report that treatment-related fatigue has a greater impact than other symptoms, including pain, nausea, and depression. Thus, management of fatigue is recognized as an important component of care for patients with cancer. Treatment of advanced and metastatic renal cell carcinoma (RCC) was, until recently, limited to cytokine-based therapies, which are associated with modest response rates and significant toxicity, including high rates of treatment-related fatigue. The paradigm for RCC treatment has shifted dramatically in the last 5 years with the advent of efficacious targeted therapies. These agents provide the promise of better tolerability because of their more selective mechanisms of action. However, there is considerable variation in the selectivity of targeted agents for RCC, and a review of randomized clinical trials in patients with advanced and/or metastatic disease reveals that there is considerable variation in the tolerability of these agents. Fatigue remains a prominent toxicity with current targeted therapies. Future agents that show better selectivity and potency than current targeted therapies should help to provide better efficacy and tolerability..
Swanton, C.
Larkin, J.M.
Gerlinger, M.
Eklund, A.C.
Howell, M.
Stamp, G.
Downward, J.
Gore, M.
Futreal, P.A.
Escudier, B.
Andre, F.
Albiges, L.
Beuselinck, B.
Oudard, S.
Hoffmann, J.
Gyorffy, B.
Torrance, C.J.
Boehme, K.A.
Volkmer, H.
Toschi, L.
Nicke, B.
Beck, M.
Szallasi, Z.
(2010). Predictive biomarker discovery through the parallel integration of clinical trial and functional genomics datasets. Genome medicine,
Vol.2.
Pickering, L.M.
Pyle, L.
Larkin, J.M.
(2009). Sunitinib is superior to interferon alpha with respect to quality of life for patients with renal cell carcinoma. Nat clin pract oncol,
Vol.6
(1),
pp. 6-7.
show abstract
Randomized trials have shown that both anti-vascular endothelial growth factor (VEGF) therapy and inhibition of the mammalian target of rapamycin have superior clinical efficacy when compared with interferon alpha in the first-line treatment of advanced renal cell carcinoma. In 2007, a pivotal phase III trial randomly allocated 750 patients with advanced renal cell carcinoma to receive either the VEGF-receptor tyrosine kinase inhibitor sunitinib or interferon alpha, and showed that sunitinib led to improved response rates, progression-free and overall survival. In this Practice Point, we discuss the data reported by Cella et al., which showed that the quality of life of patients in this trial was better with sunitinib than interferon alpha; these differences were predominantly due to better control of disease-related symptoms by sunitinib. This landmark study is the first to report comparative quality-of-life data for an anti-VEGF therapy and a cytokine therapy..
Larkin, J.M.
Clarke, R.E.
Pickering, L.M.
(2009). Everolimus (RAD001) in the treatment of advanced renal cell carcinoma: biology and pathways. Medical oncology,
Vol.26,
pp. 40-45.
Larkin, J.M.
Kipps, E.L.
Powell, C.J.
Swanton, C.
(2009). Systemic therapy for advanced renal cell carcinoma. Ther adv med oncol,
Vol.1
(1),
pp. 15-27.
show abstract
Renal cell carcinoma (RCC) accounts for approximately 3% of all cancers and is refractory to cytotoxic chemotherapy - immunotherapy has until recently been the standard of care for advanced disease. Randomised trials reported in the last 5 years have demonstrated that a number of agents including the monoclonal antibody, bevacizumab, and the kinase inhibitors - sorafenib sunitinib, temsirolimus and everolimus - are active in advanced RCC. Bevacizumab is directed against the vascular endothelial growth factor (VEGF), a key mediator of angiogenesis, whilst sorafenib and sunitinib inhibit a number of targets including the VEGF and platelet-derived growth factor (PDGFR) receptor tyrosine kinases. Temsirolimus and everolimus inhibit the intracellular mammalian target of rapamycin (mTOR) kinase. Sunitinib and temsirolimus have demonstrated efficacy in comparison with immunotherapy in the first-line setting in patients with favourable and poor prognosis advanced disease respectively. In the second-line setting, everolimus has shown benefit over placebo in patients who progress following treatment with a VEGF receptor tyrosine kinase inhibitor and sorafenib has demonstrated efficacy in comparison with placebo in patients with immunotherapy-refractory disease. We review here recent clinical trial data and discuss future developments in the systemic treatment of RCC including combination and sequential therapy, adjuvant therapy, the role of biomarkers and the prospects for the development of rational mechanism-directed therapy in this disease..
Sternberg, C.N.
Bellmunt, J.
Gruenwald, V.
Larkin, J.
Mulders, P.
(2009). Advances in the Management of Metastatic Renal Cell Cancer. European urology supplements,
Vol.8
(9),
pp. 758-761.
Larkin, J.
Gore, M.
(2009). HEALTH POLICY The UK 'postcode lottery' in renal cell carcinoma. Nature reviews urology,
Vol.6
(12),
pp. 636-638.
Miller, R.E.
Larkin, J.M.
(2009). Combination systemic therapy for advanced renal cell carcinoma. Oncologist,
Vol.14
(12),
pp. 1218-1224.
show abstract
Outcomes for patients with advanced renal cell carcinoma (RCC) have improved significantly in recent years with the development of novel noncytotoxic systemic therapies. The multitargeted kinase inhibitors sunitinib and sorafenib have been approved for the treatment of advanced RCC, and bevacizumab, a monoclonal anti-vascular endothelial growth factor antibody, has shown significant clinical activity, both as a single agent and in combination with interferon-alpha. The mammalian target of rapamycin inhibitors temsirolimus and everolimus have led to longer overall survival times in poor-risk patients in the first-line setting and longer progression-free survival times in kinase inhibitor refractory patients in the second-line setting, respectively. Despite these advances, almost all patients develop resistance to treatment and cure is rarely seen. There is therefore a need to overcome resistance, induce longer lasting remissions, and improve survival. A potential approach to this is to combine active agents, and the clinical data for combination therapy with novel targeted agents in advanced RCC are reviewed here..
Josephs, D.H.
Hutson, T.E.
Pickering, L.M.
Larkin, J.M.
Choueiri, T.K.
Patel, T.V.
Mcdermott, D.F.
Powles, T.
Harper, P.G.
Chowdhury, S.
(2009). Efficacy and toxicity of sunitinib in patients with metastatic renal cell carcinoma (mRCC) with severe renal impairment or on haemodialysis. J clin oncol,
Vol.27
(15_suppl),
p. 5109.
show abstract
5109 Background: Sunitinib is currently a standard of care for the treatment of mRCC. Due to the inclusion criteria of clinical trials, no studies of sunitinib have enrolled patients with severe renal impairment or those undergoing haemodialysis, and thus further investigation of the effect of sunitinib in this population is required. METHODS: Clinical databases were used to identify all patients with mRCC treated with sunitinib in five institutions internationally. Medical records were searched to identify only those patients with a creatinine clearance (CLcr) of <30ml/min or who had end stage renal disease (ESRD) requiring haemodialysis. Baseline characteristics, toxicity data and progression free survival (PFS) were collected. RESULTS: 21 patients met inclusion criteria with 9 (43%) undergoing haemodialysis. Baseline characteristics include a median age of 62 years (range 44-80); 90% of patients had ECOG PS of 0 or 1; 38% of patients had > 2 metastatic sites and 86% had prior nephrectomy. The estimated median PFS of this cohort was 38 weeks (range 2-120) although progression has not yet been reached in 8 (38%) patients. PR or SD was observed as best response in 17 (81%) patients. The most common treatment-related adverse events (AEs) included fatigue, diarrhoea, hand foot skin reaction (HFSR), nausea and vomiting and rash. Grade 3 treatment related AEs including fatigue, HFSR, diarrhoea and rash occurred in a total of 7 (33%) of patients. Only one patient experienced grade IV toxicity (HFSR). CONCLUSIONS: These data suggest that patients treated with sunitinib who have severe renal impairment, or ESRD on haemodialysis, have a PFS that is comparable to patients with normal renal function. In addition sunitinib appears to be reasonably well tolerated in this group of patients. These preliminary results warrant confirmation in a larger cohort of patients. [Table: see text]..
Carden, C.P.
Myerson, J.S.
Popat, S.
Montes, A.
Larkin, J.M.
Benson, M.J.
O'Brien, M.E.
(2008). Good vibrations and the power of positron thinking: positron emission tomography and endoscopic ultrasound in staging of mesothelioma-two case reports. J thorac oncol,
Vol.3
(5),
pp. 539-541.
Carden, C.P.
Larkin, J.M.
Rosenthal, M.A.
(2008). What is the risk of intracranial bleeding during anti-VEGF therapy?. Neuro oncol,
Vol.10
(4),
pp. 624-630.
show abstract
Vascular endothelial growth factor (VEGF) is a key mediator of physiological and pathological angiogenesis. All solid tumors are dependent on pathological angiogenesis, and anti-VEGF therapy has demonstrated clinical benefit in breast, colorectal, non-small-cell lung, and renal carcinomas. Central nervous system metastases are common in many of these tumor types. An increased risk of bleeding has been reported with anti-VEGF therapy, but the risk of intracranial bleeding is unknown with this type of therapy. We reviewed the available data to investigate the risk of intracranial bleeding with anti-VEGF therapy in the presence and absence of CNS metastases. The PubMed and Medline databases and the Proceedings of the American Society of Clinical Oncology (ASCO) annual meetings were searched for articles, abstracts, and presentations of clinical trials. We identified 57 trials examining the safety and efficacy of anti-VEGF therapy in a total of 10,598 patients. Four trials examined the use of anti-VEGF therapy in treating patients with brain metastases. The presence of CNS metastases was a stated exclusion criterion in 76% of trials. The rate of intracranial bleeding was negligible. We conclude that there is no trial evidence that anti-VEGF therapy confers an increased risk of intracranial bleeding, even in the presence of CNS metastases. Future trials of anti-VEGF therapy should not exclude patients with controlled CNS metastases at enrollment..
Chowdhury, S.
Larkin, J.M.
Gore, M.E.
(2008). Recent advances in the treatment of renal cell carcinoma and the role of targeted therapies. European journal of cancer,
Vol.44
(15),
pp. 2152-2161.
Dernedde, U.
Chan, S.
Sykes, H.
Oakley, C.
Larkin, J.
Popat, S.
Gilbert, D.
Jones, L.
Chowdhury, S.
(2008). South West London Cancer Network (SWLCN) audit of patients with chemotherapy-induced febrile neutropenia (CIFN). Journal of clinical oncology,
Vol.26
(15).
Larkin, J.
Gore, M.
(2008). Malignant melanoma (metastatic). Bmj clin evid,
Vol.2008.
show abstract
INTRODUCTION: Each year in the UK there are 8100 new cases of malignant melanoma, and 1800 deaths, largely as a result of metastatic disease. The median survival of people with metastatic melanoma is 6-9 months after diagnosis, with 10% of people alive at 5 years. Chemotherapy is given with palliative rather than curative intent for metastatic disease. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of chemotherapy for metastatic melanoma? What are the effects of immunotherapy for metastatic melanoma? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2007 (BMJ Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 23 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: adding interferon alfa (with or without interleukin-2) to chemotherapy; dacarbazine; single-agent or combination chemotherapy; supportive palliative care alone or with chemotherapy; and temozolomide..
Fearfield, L.A.
Larkin, J.M.
Rowe, A.
A'Hern, R.
Fisher, C.
Francis, N.
MacKie, R.
McCann, B.
Gore, M.E.
Bunker, C.B.
(2007). Expression of p16, CD95, CD95L and Helix pomatia agglutinin in relapsing and nonrelapsing very thin melanoma. British journal of dermatology,
Vol.156
(3),
pp. 440-8.
Larkin, J.M.
Porter, C.D.
(2007). Complement insufficiency limits efficacy in a xenograft model of hyperacute rejection for cancer therapy. Cancer immunology immunotherapy,
Vol.56
(1),
pp. 60-69.
Larkin, J.M.
(2007). Patupilone Antimitotic drug, microtubule-stabilizing agent, oncolytic. Drugs of the future,
Vol.32
(4),
pp. 323-336.
Larkin, J.M.
Kaye, S.B.
(2007). Potential clinical applications of epothilones: a review of phase II studies. Ann oncol,
Vol.18 Suppl 5,
pp. v28-v34.
show abstract
BACKGROUND: Epothilones are cytotoxic macrolides that share a similar mechanism of action with the taxanes but demonstrate antitumor activity in taxane-resistant settings. Six epothilones are in early clinical trials for cancer treatment. DESIGN: This review summarizes data from phase II clinical studies of the epothilones ixabepilone (BMS-247550), patupilone (EPO906), and KOS-862. Data were identified by searches of PubMed and of the proceedings of the American Society of Clinical Oncology annual meetings and the Federation of European Cancer Societies biennial conference for the period 2000-2006. Studies were included if safety and efficacy data were available for at least 10 patients with a given tumor type in a standard phase II design. RESULTS: Epothilones have demonstrated activity in lung, ovarian, breast, prostate, and renal carcinomas and in non-Hodgkin's lymphoma in phase II studies. Little or no evidence of clinical activity has been reported in studies of epothilones in other tumor types. Preliminary data indicate that epothilones can be combined safely with other cytotoxic agents such as carboplatin. CONCLUSIONS: The epothilones may play a role as an alternative to taxanes if activity in resistant settings can be confirmed together with an acceptable toxicity profile. Randomized studies are awaited to investigate the utility of epothilones in single-agent and combination regimens..
Larkin, J.M.
Chowdhury, S.
Gore, M.E.
(2007). Drug insight: advances in renal cell carcinoma and the role of targeted therapies. Nat clin pract oncol,
Vol.4
(8),
pp. 470-479.
show abstract
In metastatic renal cell carcinoma (RCC) immunotherapy results in a small but important improvement in overall survival, but a need exists to develop more-effective systemic therapies. Recent developments in our understanding of the molecular biology of RCC have identified several pathways associated with the development of the disease. A number of strategies designed specifically to target these pathways have resulted. Initial studies have shown marked clinical benefits of so-called 'targeted therapies'. Sunitinib, sorafenib and axitinib are kinase inhibitors that inhibit the VEGF, platelet-derived growth factor and c-kit receptor tyrosine kinases. Bevacizumab is a monoclonal antibody that is directed against VEGF. Temsirolimus inhibits the mammalian target of rapamycin. These agents have all shown considerable activity with manageable toxicity in phase II and III studies in both previously treated and untreated patients. In phase III studies, sorafenib and bevacizumab have been associated with prolonged progression-free survival compared with placebo. Phase III data have shown improvements in progression-free and overall survival with sunitinib and temsirolimus, respectively, compared with interferon alfa. Additional studies are needed to determine the optimum utilization of these agents at the appropriate stage of disease and in the best combinations for maximal clinical benefit..
Larkin, J.M.
Hughes, S.A.
Beirne, D.A.
Patel, P.M.
Gibbens, I.M.
Bate, S.C.
Thomas, K.
Eisen, T.G.
Gore, M.E.
(2007). A Phase I/II study of lomustine and temozolomide in patients with cerebral metastases from malignant melanoma. British journal of cancer,
Vol.96
(1),
pp. 44-48.
Larkin, J.M.
Kaye, S.B.
(2006). Epothilones in the treatment of cancer. Expert opinion on investigational drugs,
Vol.15
(6),
pp. 691-12.
Larkin, J.M.
Norsworth, P.J.
A'Hern, R.P.
Eisen, T.G.
Gore, M.E.
Porter, C.D.
(2006). Anti-alpha Gal-dependent complement-mediated cytotoxicity in metastatic melanoma. Melanoma research,
Vol.16
(2),
pp. 157-7.
Larkin, J.M.
Eisen, T.
(2006). Renal cell carcinoma and the use of sorafenib. Ther clin risk manag,
Vol.2
(1),
pp. 87-98.
show abstract
Immunotherapy results in a small overall survival advantage in metastatic renal cell carcinoma (RCC), but there is a need to develop more effective systemic therapies. Angiogenesis has an important role in the pathophysiology of RCC and vascular endothelial growth factor (VEGF) is a key mediator of this process. Sorafenib (BAY 43-9006) is a new agent belonging to a class of drugs called kinase inhibitors and inhibits the VEGF, platelet-derived growth factor (PDGF), and c-KIT receptor tyrosine kinases, amongst others. Sorafenib has shown significant activity with manageable toxicity in metastatic RCC in phase 2 studies in patients pretreated with immunotherapy, whilst prolonged progression-free survival in comparison with placebo in a phase 3 study has been reported. Further phase 3 trials in advanced disease are ongoing and a trial of adjuvant sorafenib therapy in RCC is planned..
Larkin, J.M.
Eisen, T.
(2006). Kinase inhibitors in the treatment of renal cell carcinoma. Crit rev oncol hematol,
Vol.60
(3),
pp. 216-226.
show abstract
Immunotherapy confers a small but significant overall survival advantage in metastatic renal cell carcinoma (RCC) but a need exists to develop more effective systemic therapies. Angiogenesis has a key role in the pathophysiology of renal cell carcinoma and vascular endothelial growth factor (VEGF) is an important mediator of this process. Sunitinib, sorafenib and axitinib are new agents which belong to a class of drugs called kinase inhibitors and inhibit the VEGF, platelet-derived growth factor (PDGF) and c-KIT receptor tyrosine kinases. Temsirolimus inhibits the mammalian target of rapamycin (mTOR). All these agents have shown significant activity with manageable toxicity in metastatic RCC in phase 2 studies in patients generally pretreated with immunotherapy, whilst prolonged progression-free survival in a phase 3 study has been reported with sorafenib in comparison with placebo. Further phase 3 trials are recruiting and the combination of kinase inhibitors with other therapies is under investigation..
Larkin, J.M.
Porter, C.D.
(2005). Mice are unsuitable for modelling ABO discordance despite strain-specific A cross-reactive natural IgM. British journal of haematology,
Vol.130
(2),
pp. 310-317.
Larkin, J.M.
Gore, M.E.
(2005). The MRC randomised-controlled trial of interferon-alpha, interleukin-2 and 5-fluorouracil vs interferon-alpha alone in patients with advanced renal cell carcinoma (RE04): Rationale and progress. Clinical oncology,
Vol.17
(5),
pp. 319-321.
Kolomainen, D.F.
Larkin, J.M.
Badran, M.
A'Hern, R.P.
King, D.M.
Fisher, C.
Bridges, J.E.
Blake, P.R.
Barton, D.P.
Shepherd, J.H.
Kaye, S.B.
Gore, M.E.
(2002). Epithelial ovarian cancer metastasizing to the brain: a late manifestation of the disease with an increasing incidence. J clin oncol,
Vol.20
(4),
pp. 982-986.
show abstract
PURPOSE: We present the Royal Marsden Hospital experience of cerebral metastases from primary epithelial ovarian carcinoma (EOC) over the last 20 years and examine the evidence for an increasing incidence of EOC metastasizing to this site. PATIENTS AND METHODS: A total of 3,690 women with EOC were seen at the Royal Marsden Hospital from 1980 to 2000. Eighteen of these patients developed cerebral metastases. RESULTS: Median age at diagnosis of EOC was 52 years (range, 39 to 67). All patients received at least one line of platinum-based chemotherapy; 56% (10 of 18) received more than one line of treatment; 17% (three of 18), two lines; 11% (two of 18), three lines; and 28% (five of 18), four lines. The median treatment interval between each line of chemotherapy was 12, 18, and 4 months. The median interval between diagnosis and CNS relapse was 46 months (range, 12 to 113), in comparison with 5 and 7.5 months for hematogenous relapse in lung or liver, respectively (P <.001). The incidence of CNS metastases in our population from 1980 to 1984 was 0.2%; from 1985 to 1989, 0%; from 1990 to 1994, 0.3%; and from 1995 to 1999, 1.3% (P <.001). An analysis of data from the literature also suggests that the incidence of cerebral metastases from EOC has increased over time. CONCLUSION: CNS metastases in EOC are a rare and late manifestation of the disease, occurring in patients with a prolonged survival caused by repeated chemosensitive relapses. An analysis of our data and the data from the literature suggests that the incidence of metastasis at this site in patients with EOC is increasing..
Kolomainen, D.F.
Larkin, J.M.
Badran, M.
A’Hern, R.P.
King, D.M.
Fisher, C.
Bridges, J.E.
Blake, P.R.
Barton, D.P.
Shepherd, J.H.
Kaye, S.B.
Gore, M.E.
(2002). Epithelial Ovarian Cancer Metastasizing to the Brain: A Late Manifestation of the Disease With an Increasing Incidence. Journal of clinical oncology,
Vol.20
(4),
pp. 982-986.
show abstract
PURPOSE: We present the Royal Marsden Hospital experience of cerebral metastases from primary epithelial ovarian carcinoma (EOC) over the last 20 years and examine the evidence for an increasing incidence of EOC metastasizing to this site. PATIENTS AND METHODS: A total of 3,690 women with EOC were seen at the Royal Marsden Hospital from 1980 to 2000. Eighteen of these patients developed cerebral metastases. RESULTS: Median age at diagnosis of EOC was 52 years (range, 39 to 67). All patients received at least one line of platinum-based chemotherapy; 56% (10 of 18) received more than one line of treatment; 17% (three of 18), two lines; 11% (two of 18), three lines; and 28% (five of 18), four lines. The median treatment interval between each line of chemotherapy was 12, 18, and 4 months. The median interval between diagnosis and CNS relapse was 46 months (range, 12 to 113), in comparison with 5 and 7.5 months for hematogenous relapse in lung or liver, respectively (P < .001). The incidence of CNS metastases in our population from 1980 to 1984 was 0.2%; from 1985 to 1989, 0%; from 1990 to 1994, 0.3%; and from 1995 to 1999, 1.3% (P < .001). An analysis of data from the literature also suggests that the incidence of cerebral metastases from EOC has increased over time. CONCLUSION: CNS metastases in EOC are a rare and late manifestation of the disease, occurring in patients with a prolonged survival caused by repeated chemosensitive relapses. An analysis of our data and the data from the literature suggests that the incidence of metastasis at this site in patients with EOC is increasing. .
Gulati, S.
Martinez, P.
Joshi, T.
Birbak, N.J.
Santos, C.R.
Rowan, A.J.
Pickering, L.
Gore, M.
Larkin, J.
Szallasi, Z.
Bates, P.A.
Swanton, C.
Gerlinger, M.
Systematic Evaluation of the Prognostic Impact and Intratumour Heterogeneity of Clear Cell Renal Cell Carcinoma Biomarkers. European urology,
.
show abstract
Background: Candidate biomarkers have been identified for clear cell renal cell carcinoma (ccRCC) patients, but most have not been validated.
Objective: To validate published ccRCC prognostic biomarkers in an independent patient cohort and to assess intratumour heterogeneity (ITH) of the most promising markers to guide biomarker optimisation.
Design, setting, and participants: Cancer-specific survival (CSS) for each of 28 identified genetic or transcriptomic biomarkers was assessed in 350 ccRCC patients. ITH was interrogated in a multiregion biopsy data set of 10 ccRCCs.
Outcome measurements and statistical analysis: Biomarker association with CSS was analysed by univariate and multivariate analyses.
Results and limitations: A total of 17 of 28 biomarkers (TP53 mutations; amplifications of chromosomes 8q, 12, 20q11.21q13.32, and 20 and deletions of 4p, 9p, 9p21.3p24.1, and 22q; low EDNRB and TSPAN7 expression and six gene expression signatures) were validated as predictors of poor CSS in univariate analysis. Tumour stage and the ccB expression signature were the only independent predictors in multivariate analysis. ITH of the ccB signature was identified in 8 of 10 tumours. Several genetic alterations that were significant in univariate analysis were enriched, and chromosomal instability indices were increased in samples expressing the ccB signature. The study may be underpowered to validate low-prevalence biomarkers.
Conclusions: The ccB signature was the only independent prognostic biomarker. Enrichment of multiple poor prognosis genetic alterations in ccB samples indicated that several events may be required to establish this aggressive phenotype, catalysed in some tumours by chromosomal instability. Multiregion assessment may improve the precision of this biomarker..
Henrion, M.Y.
Purdue, M.P.
Scelo, G.
Broderick, P.
Frampton, M.
Ritchie, A.
Meade, A.
Li, P.
McKay, J.
Johansson, M.
Lathrop, M.
Larkin, J.
Rothman, N.
Wang, Z.
Chow, W.-.
Stevens, V.L.
Diver, W.R.
Albanes, D.
Virtamo, J.
Brennan, P.
Eisen, T.
Chanock, S.
Houlston, R.S.
Common Variation at 1q24 1 (ALDH9A1) Is a Potential Risk Factor for Renal Cancer. Plos one,
Vol.10
(3),
pp. e0122589-e0122589.
Biondo, A.
Alexander, H.
Khabra, K.
Pickering, L.
Gore, M.
Larkin, J.
Pazopanib-Induced Alopecia, an Underestimated Toxicity?. Frontiers in oncology,
Vol.5.
Eggermont, A.M.
Blank, C.U.
Mandala, M.
Long, G.V.
Atkinson, V.
Dalle, S.
Haydon, A.
Lichinitser, M.
Khattak, A.
Carlino, M.S.
Sandhu, S.
Larkin, J.
Puig, S.
Ascierto, P.A.
Rutkowski, P.
Schadendorf, D.
Koornstra, R.
Hernandez-Aya, L.
Maio, M.
van den Eertwegh, A.J.
Grob, J.-.
Gutzmer, R.
Jamal, R.
Lorigan, P.
Ibrahim, N.
Marreaud, S.
van Akkooi, A.C.
Suciu, S.
Robert, C.
Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. The new england journal of medicine,
Vol.378
(19),
pp. 1789-1801.
show abstract
BACKGROUND:The programmed death 1 (PD-1) inhibitor pembrolizumab has been found to prolong progression-free and overall survival among patients with advanced melanoma. We conducted a phase 3 double-blind trial to evaluate pembrolizumab as adjuvant therapy in patients with resected, high-risk stage III melanoma. METHODS:Patients with completely resected stage III melanoma were randomly assigned (with stratification according to cancer stage and geographic region) to receive 200 mg of pembrolizumab (514 patients) or placebo (505 patients) intravenously every 3 weeks for a total of 18 doses (approximately 1 year) or until disease recurrence or unacceptable toxic effects occurred. Recurrence-free survival in the overall intention-to-treat population and in the subgroup of patients with cancer that was positive for the PD-1 ligand (PD-L1) were the primary end points. Safety was also evaluated. RESULTS:At a median follow-up of 15 months, pembrolizumab was associated with significantly longer recurrence-free survival than placebo in the overall intention-to-treat population (1-year rate of recurrence-free survival, 75.4% [95% confidence interval {CI}, 71.3 to 78.9] vs. 61.0% [95% CI, 56.5 to 65.1]; hazard ratio for recurrence or death, 0.57; 98.4% CI, 0.43 to 0.74; P<0.001) and in the subgroup of 853 patients with PD-L1-positive tumors (1-year rate of recurrence-free survival, 77.1% [95% CI, 72.7 to 80.9] in the pembrolizumab group and 62.6% [95% CI, 57.7 to 67.0] in the placebo group; hazard ratio, 0.54; 95% CI, 0.42 to 0.69; P<0.001). Adverse events of grades 3 to 5 that were related to the trial regimen were reported in 14.7% of the patients in the pembrolizumab group and in 3.4% of patients in the placebo group. There was one treatment-related death due to myositis in the pembrolizumab group. CONCLUSIONS:As adjuvant therapy for high-risk stage III melanoma, 200 mg of pembrolizumab administered every 3 weeks for up to 1 year resulted in significantly longer recurrence-free survival than placebo, with no new toxic effects identified. (Funded by Merck; ClinicalTrials.gov number, NCT02362594 ; EudraCT number, 2014-004944-37 .)..
Argyropulo-Palmer, M.
Jenkins, A.
Theti, D.S.
Larkin, J.
Montgomery, D.
Sunitinib in Metastatic Renal Cell Carcinoma: A Systematic Review of UK Real World Data. Frontiers in oncology,
Vol.5.
Larkin, J.
Hatswell, A.J.
Nathan, P.
Lebmeier, M.
Lee, D.
The Predicted Impact of Ipilimumab Usage on Survival in Previously Treated Advanced or Metastatic Melanoma in the UK. Plos one,
Vol.10
(12),
pp. e0145524-e0145524.
Wolchok, J.D.
Chiarion-Sileni, V.
Gonzalez, R.
Grob, J.-.
Rutkowski, P.
Lao, C.D.
Cowey, C.L.
Schadendorf, D.
Wagstaff, J.
Dummer, R.
Ferrucci, P.F.
Smylie, M.
Butler, M.O.
Hill, A.
Márquez-Rodas, I.
Haanen, J.B.
Guidoboni, M.
Maio, M.
Schöffski, P.
Carlino, M.S.
Lebbé, C.
McArthur, G.
Ascierto, P.A.
Daniels, G.A.
Long, G.V.
Bas, T.
Ritchings, C.
Larkin, J.
Hodi, F.S.
Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone Versus Ipilimumab in Patients With Advanced Melanoma. Journal of clinical oncology : official journal of the american society of clinical oncology,
Vol.40
(2),
pp. 127-137.
show abstract
Purpose
In the phase III CheckMate 067 trial, durable clinical benefit was demonstrated previously with nivolumab plus ipilimumab and nivolumab alone versus ipilimumab. Here, we report 6.5-year efficacy and safety outcomes.
Patients and methods
Patients with previously untreated unresectable stage III or stage IV melanoma were randomly assigned 1:1:1 to receive nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks (four doses) followed by nivolumab 3 mg/kg once every 2 weeks (n = 314), nivolumab 3 mg/kg once every 2 weeks (n = 316), or ipilimumab 3 mg/kg once every 3 weeks (four doses; n = 315). Coprimary end points were progression-free survival and overall survival (OS) with nivolumab plus ipilimumab or nivolumab versus ipilimumab. Secondary end points included objective response rate, descriptive efficacy assessments of nivolumab plus ipilimumab versus nivolumab alone, and safety. Melanoma-specific survival (MSS; descriptive analysis), which excludes deaths unrelated to melanoma, was also evaluated.
Results
Median OS (minimum follow-up, 6.5 years) was 72.1, 36.9, and 19.9 months in the combination, nivolumab, and ipilimumab groups, respectively. Median MSS was not reached, 58.7, and 21.9 months, respectively; 6.5-year OS rates were 57%, 43%, and 25% in patients with
BRAF-mutant tumors and 46%, 42%, and 22% in those with
BRAF-wild-type tumors, respectively. In patients who discontinued treatment, the median treatment-free interval was 27.6, 2.3, and 1.9 months, respectively. Since the 5-year analysis, no new safety signals were observed.
Conclusion
These 6.5-year CheckMate 067 results, which include the longest median OS in a phase III melanoma trial reported to date and the first report of MSS, showed durable, improved clinical outcomes with nivolumab plus ipilimumab or nivolumab versus ipilimumab in patients with advanced melanoma and, in descriptive analyses, with the combination over nivolumab monotherapy..
Fendler, A.
Au, L.
Shepherd, S.T.
Byrne, F.
Cerrone, M.
Boos, L.A.
Rzeniewicz, K.
Gordon, W.
Shum, B.
Gerard, C.L.
Ward, B.
Xie, W.
Schmitt, A.M.
Joharatnam-Hogan, N.
Cornish, G.H.
Pule, M.
Mekkaoui, L.
Ng, K.W.
Carlyle, E.
Edmonds, K.
Rosario, L.D.
Sarker, S.
Lingard, K.
Mangwende, M.
Holt, L.
Ahmod, H.
Stone, R.
Gomes, C.
Flynn, H.R.
Agua-Doce, A.
Hobson, P.
Caidan, S.
Howell, M.
Wu, M.
Goldstone, R.
Crawford, M.
Cubitt, L.
Patel, H.
Gavrielides, M.
Nye, E.
Snijders, A.P.
MacRae, J.I.
Nicod, J.
Gronthoud, F.
Shea, R.L.
Messiou, C.
Cunningham, D.
Chau, I.
Starling, N.
Turner, N.
Welsh, L.
van As, N.
Jones, R.L.
Droney, J.
Banerjee, S.
Tatham, K.C.
Jhanji, S.
O’Brien, M.
Curtis, O.
Harrington, K.
Bhide, S.
Bazin, J.
Robinson, A.
Stephenson, C.
Slattery, T.
Khan, Y.
Tippu, Z.
Leslie, I.
Gennatas, S.
Okines, A.
Reid, A.
Young, K.
Furness, A.J.
Pickering, L.
Gandhi, S.
Gamblin, S.
Swanton, C.
Nicholson, E.
Kumar, S.
Yousaf, N.
Wilkinson, K.A.
Swerdlow, A.
Harvey, R.
Kassiotis, G.
Larkin, J.
Wilkinson, R.J.
Turajlic, S.
Functional antibody and T cell immunity following SARS-CoV-2 infection, including by variants of concern, in patients with cancer: the CAPTURE study. Nature cancer,
Vol.2
(12),
pp. 1321-1337.
show abstract
AbstractPatients with cancer have higher COVID-19 morbidity and mortality. Here we present the prospective CAPTURE study, integrating longitudinal immune profiling with clinical annotation. Of 357 patients with cancer, 118 were SARS-CoV-2 positive, 94 were symptomatic and 2 died of COVID-19. In this cohort, 83% patients had S1-reactive antibodies and 82% had neutralizing antibodies against wild type SARS-CoV-2, whereas neutralizing antibody titers against the Alpha, Beta and Delta variants were substantially reduced. S1-reactive antibody levels decreased in 13% of patients, whereas neutralizing antibody titers remained stable for up to 329 days. Patients also had detectable SARS-CoV-2-specific T cells and CD4+ responses correlating with S1-reactive antibody levels, although patients with hematological malignancies had impaired immune responses that were disease and treatment specific, but presented compensatory cellular responses, further supported by clinical recovery in all but one patient. Overall, these findings advance the understanding of the nature and duration of the immune response to SARS-CoV-2 in patients with cancer..
Lidington, E.
Darlington, A.S.
Vlooswijk, C.
Beardsworth, S.
McCaffrey, S.
Tang, S.
Stallard, K.
Younger, E.
Edwards, P.
Ali, A.I.
Nandhabalan, M.
Din, A.
Starling, N.
Larkin, J.
Stanway, S.
Nobbenhuis, M.
Banerjee, S.
Szucs, Z.
Gonzalez, M.
Sirohi, B.
Husson, O.
van der Graaf, W.T.
Beyond Teenage and Young Adult Cancer Care: Care Experiences of Patients Aged 25-39 Years Old in the UK National Health Service. Clinical oncology (royal college of radiologists (great britain)),
Vol.33
(8),
pp. 494-506.
show abstract
Aims Adolescents and young adults aged 15-39 years with cancer face unique medical, practical and psychosocial issues. In the UK, principal treatment centres and programmes have been designed to care for teenage and young adult patients aged 13-24 years in an age-appropriate manner. However, for young adults (YAs) aged 25-39 years with cancer, little access to age-specific support is available. The aim of this study was to examine this possible gap by qualitatively exploring YA care experiences, involving patients as research partners in the analysis to ensure robust results. Materials and methods We conducted a phenomenological qualitative study with YAs diagnosed with any cancer type between ages 25 and 39 years old in the last 5 years. Participants took part in interviews or focus groups and data were analysed using inductive thematic analysis. Results were shaped in an iterative process with the initial coders and four YA patients who did not participate in the study to improve the rigor of the results. Results Sixty-five YAs with a range of tumour types participated. We identified seven themes and 13 subthemes. YAs found navigating the healthcare system difficult and commonly experienced prolonged diagnostic pathways. Participants felt under-informed about clinical details and the long-term implications of side-effects on daily life. YAs found online resources overwhelming but also a source of information and treatment support. Some patients regretted not discussing fertility before cancer treatment or felt uninformed or rushed when making fertility preservation decisions. A lack of age-tailored content or age-specific groups deterred YAs from accessing psychological support and rehabilitation services. Conclusions YAs with cancer may miss some benefits provided to teenagers and young adults in age-tailored cancer services. Improving services for YAs in adult settings should focus on provision of age-specific information and access to existing relevant support..
Alexander, J.L.
Ibraheim, H.
Sheth, B.
Little, J.
Khan, M.S.
Richards, C.
Hunter, N.
Chauhan, D.
Ratnakumaran, R.
McHugh, K.
Pinato, D.J.
Nathan, P.
Choy, J.
Crusz, S.M.
Furness, A.
Turajlic, S.
Pickering, L.
Larkin, J.
Teare, J.P.
Papa, S.
Speight, A.
Sharma, A.
Powell, N.
Clinical outcomes of patients with corticosteroid refractory immune checkpoint inhibitor-induced enterocolitis treated with infliximab. Journal for immunotherapy of cancer,
Vol.9
(7).
show abstract
Introduction Immune checkpoint inhibitors (CPIs) have changed the treatment landscape for many cancers, but also cause severe inflammatory side effects including enterocolitis. CPI-induced enterocolitis is treated empirically with corticosteroids, and infliximab (IFX) is used in corticosteroid-refractory cases. However, robust outcome data for these patients are scarce.Methods We conducted a multicenter (six cancer centers), cohort study of outcomes in patients treated with IFX for corticosteroid-refractory CPI-induced enterocolitis between 2007 and 2020. The primary outcome was corticosteroid-free clinical remission (CFCR) with Common Terminology Criteria for Adverse Events (CTCAE) grade 0 for diarrhea at 12 weeks after IFX initiation. We also assessed cancer outcomes at 1 year using RECIST V1.1 criteria.Results 127 patients (73 male; median age 59 years) were treated with IFX for corticosteroid-refractory CPI-induced enterocolitis. Ninety-six (75.6%) patients had diarrhea CTCAE grade >2 and 115 (90.6%) required hospitalization for colitis. CFCR was 41.2% at 12 weeks and 50.9% at 26 weeks. In multivariable logistic regression, IFX-resistant enterocolitis was associated with rectal bleeding (OR 0.19; 95% CI 0.04 to 0.80; p=0.03) and absence of colonic crypt abscesses (OR 2.16; 95% CI 1.13 to 8.05; p=0.03). Cancer non-progression was significantly more common in patients with IFX-resistant enterocolitis (64.4%) as compared with patients with IFX-responsive enterocolitis (37.5%; p=0.013).Conclusion This is the largest study to date reporting outcomes of IFX therapy in patients with corticosteroid-refractory CPI-induced enterocolitis. Using predefined robust endpoints, we have demonstrated that fewer than half of patients achieved CFCR. Our data also indicate that cancer outcomes may be better in patients developing prolonged and severe inflammatory side effects of CPI therapy..
Au, L.
Hatipoglu, E.
Robert de Massy, M.
Litchfield, K.
Beattie, G.
Rowan, A.
Schnidrig, D.
Thompson, R.
Byrne, F.
Horswell, S.
Fotiadis, N.
Hazell, S.
Nicol, D.
Shepherd, S.T.
Fendler, A.
Mason, R.
Del Rosario, L.
Edmonds, K.
Lingard, K.
Sarker, S.
Mangwende, M.
Carlyle, E.
Attig, J.
Joshi, K.
Uddin, I.
Becker, P.D.
Sunderland, M.W.
Akarca, A.
Puccio, I.
Yang, W.W.
Lund, T.
Dhillon, K.
Vasquez, M.D.
Ghorani, E.
Xu, H.
Spencer, C.
López, J.I.
Green, A.
Mahadeva, U.
Borg, E.
Mitchison, M.
Moore, D.A.
Proctor, I.
Falzon, M.
Pickering, L.
Furness, A.J.
Reading, J.L.
Salgado, R.
Marafioti, T.
Jamal-Hanjani, M.
PEACE Consortium,
Kassiotis, G.
Chain, B.
Larkin, J.
Swanton, C.
Quezada, S.A.
Turajlic, S.
TRACERx Renal Consortium,
Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma. Cancer cell,
Vol.39
(11),
pp. 1497-1518.e11.
show abstract
ADAPTeR is a prospective, phase II study of nivolumab (anti-PD-1) in 15 treatment-naive patients (115 multiregion tumor samples) with metastatic clear cell renal cell carcinoma (ccRCC) aiming to understand the mechanism underpinning therapeutic response. Genomic analyses show no correlation between tumor molecular features and response, whereas ccRCC-specific human endogenous retrovirus expression indirectly correlates with clinical response. T cell receptor (TCR) analysis reveals a significantly higher number of expanded TCR clones pre-treatment in responders suggesting pre-existing immunity. Maintenance of highly similar clusters of TCRs post-treatment predict response, suggesting ongoing antigen engagement and survival of families of T cells likely recognizing the same antigens. In responders, nivolumab-bound CD8+ T cells are expanded and express GZMK/B. Our data suggest nivolumab drives both maintenance and replacement of previously expanded T cell clones, but only maintenance correlates with response. We hypothesize that maintenance and boosting of a pre-existing response is a key element of anti-PD-1 mode of action..
Fu, X.
Zhao, Y.
Lopez, J.I.
Rowan, A.
Au, L.
Fendler, A.
Hazell, S.
Xu, H.
Horswell, S.
Shepherd, S.T.
Spencer, C.E.
Spain, L.
Byrne, F.
Stamp, G.
O'Brien, T.
Nicol, D.
Augustine, M.
Chandra, A.
Rudman, S.
Toncheva, A.
Furness, A.J.
Pickering, L.
Kumar, S.
Koh, D.-.
Messiou, C.
Dafydd, D.A.
Orton, M.R.
Doran, S.J.
Larkin, J.
Swanton, C.
Sahai, E.
Litchfield, K.
Turajlic, S.
TRACERx Renal Consortium,
Bates, P.A.
Spatial patterns of tumour growth impact clonal diversification in a computational model and the TRACERx Renal study. Nature ecology & evolution,
Vol.6
(1),
pp. 88-102.
show abstract
Genetic intra-tumour heterogeneity fuels clonal evolution, but our understanding of clinically relevant clonal dynamics remain limited. We investigated spatial and temporal features of clonal diversification in clear cell renal cell carcinoma through a combination of modelling and real tumour analysis. We observe that the mode of tumour growth, surface or volume, impacts the extent of subclonal diversification, enabling interpretation of clonal diversity in patient tumours. Specific patterns of proliferation and necrosis explain clonal expansion and emergence of parallel evolution and microdiversity in tumours. In silico time-course studies reveal the appearance of budding structures before detectable subclonal diversification. Intriguingly, we observe radiological evidence of budding structures in early-stage clear cell renal cell carcinoma, indicating that future clonal evolution may be predictable from imaging. Our findings offer a window into the temporal and spatial features of clinically relevant clonal evolution..
Gudd, C.L.
Au, L.
Triantafyllou, E.
Shum, B.
Liu, T.
Nathwani, R.
Kumar, N.
Mukherjee, S.
Dhar, A.
Woollard, K.J.
Yone, Y.
Pinato, D.J.
Thursz, M.R.
Goldin, R.D.
Gore, M.E.
Larkin, J.
Khamri, W.
Antoniades, C.G.
Turajlic, S.
Possamai, L.A.
Activation and transcriptional profile of monocytes and CD8+ T cells are altered in checkpoint inhibitor-related hepatitis. Journal of hepatology,
Vol.75
(1),
pp. 177-189.
show abstract
Background & aims Checkpoint inhibitor-related hepatitis (CPI-Hep) is an emerging clinical challenge. We aimed to gain insights into the immunopathology of CPI-Hep by comprehensively characterising myeloid and lymphoid subsets.Methods CPI-treated patients with or without related hepatitis (CPI-Hep; n = 22 and CPI-noHep; n = 7) were recruited. Phenotypic and transcriptional profiling of peripheral immune subsets was performed and compared with 19 healthy controls (HCs). In vitro monocyte-derived macrophages (MoMFs) were assessed for activation and cytokine production. CD163, CCR2, CD68, CD3, CD8 and granzyme B expression was assessed using immunohistochemistry/immunofluorescence (n = 4).Results A significant total monocyte depletion was observed in CPI-Hep compared with HCs (p = 0.04), along with a proportionate increase in the classical monocyte population (p = 0.0002) and significant upregulation of CCR2, CD163 and downregulation of CCR7. Soluble CD163 levels were significantly elevated in CPI-Hep compared with HCs (p <0.0001). In vitro MoMFs from CPI-Hep showed enhanced production of pro-inflammatory cytokines. CD8 + T cells demonstrated increased perforin, granzyme B, ICOS and HLA-DR expression in CPI-Hep. Transcriptional profiling indicated the presence of activated monocyte and enhanced effector CD8 + T cell populations in CPI-Hep. Immunohistochemistry demonstrated co-localisation of CD8 + /granzyme B + T cells with CD68 + CCR2 + /CD68 + CD163 + macrophages in CPI-Hep liver tissue.Conclusions CPI-Hep is associated with activation of peripheral monocytes and an enhanced cytotoxic, effector CD8 + T cell phenotype. These changes were reflected by liver inflammation composed of CD163 + /CCR2 + macrophages and CD8 + T cells.Lay summary Some patients who receive immunotherapy for cancer develop liver inflammation, which requires cessation of cancer treatment. Herein, we describe ways in which the white blood cells of patients who develop liver inflammation differ from those of patients who receive the same immunotherapy but do not experience liver-related side effects. Targeting some of the pathways we identify may help to prevent or manage this side effect and facilitate cancer treatment..